Progress on Priority 1: Model Resources to Advance the Study of Human Diseases
Programs and Activities Highlights
- Notice of Funding Opportunity: Informatics, Coordination and Service Center for the Mutant Mouse Resource and Research Centers (U42 Clinical Trial Not Allowed)
The purpose of this notice of funding opportunity is to provide continuing support for the Informatics, Coordination and Service Center (ICSC) unit of the Mutant Mouse Resource and Research Centers (MMRRC) consortium. The ICSC is expected to provide informatics and coordinating services to the MMRRC consortium and biomedical researchers. The announcement includes a requirement for the center’s close coordination with efforts to develop new approach methodologies (NAMs) that complement traditional animal-based research. These include cell culture, organoids, computational models, and microphysiological systems. Proposed activities should include collection and analysis of comparative information on the use of NAMs that enhance the predictive power of human disease models and support their integration with traditional models. - Notice of Funding Opportunity: Resource-Related Research Projects for Development of Models and Related Materials for Studying Human Health and Diseases (R24 Clinical Trials Not Allowed)
ORIP encourages grant applications aimed at developing, characterizing, or improving research models for human health and diseases; developing biology-based new approach methodologies (NAMs) applicable to human health and diseases; or improving access to information about or generated from the use of models for human disease. The models, including NAMs, and related biological materials developed must be broadly applicable to the scientific interests of two or more NIH institutes or centers and must evaluate diseases and processes that impact multiple organ systems in alignment with ORIP’s NIH-wide mission and programs. - Precision Model Centers Introductory Meeting
ORIP organized and presented at the Precision Model Centers Introductory Meeting on September 15, 2025. This virtual meeting included principal investigators and project leads of ORIP’s renewed U54 Division of Comparative Medicine (DCM) initiative, the Precision Model Centers Consortium. Program officials of the projects (DCM) and project scientists (Division of Construction and Instruments) attended the meeting, presented the plan for the new cycle, discussed collaborations, and planned future meetings. - International Mouse Phenotyping Consortium Network Call
An ORIP staff member presented an NIH update on new approach methodologies (NAMs) and the use of animals in research at the International Mouse Phenotyping Consortium (IMPC) network call on August 12, 2025. The IMPC monthly call includes members of the IMPC, as well as NIH staff. ORIP’s presentation was devoted to the current NIH policies regarding use of animals in research, as well as NAM initiatives. Attendees discussed implementation of the policies and their potential effect on Knockout Mouse Project/IMPC activities. - Cryopreservation Workshop, Session V: Long-Term Preservation Methods for Nonhuman Primate Models in Biomedical Research
ORIP hosted the Cryopreservation and Other Preservation Approaches for Animal Models Workshop to address topics related to cryopreservation and other preservation methods. Session V, held on July 15, 2025, focused on long-term preservation of nonhuman primate models for biomedical research. This session brought together experts in the field to discuss current state-of-the-art techniques, as well as challenges and barriers in the field. A summary of the workshop will be posted on the ORIP website. - Wonderous Worms: Unearthing New Insights Into Health
NIH News in Health published an article titled “Wonderous Worms: Unearthing New Insights Into Health” in July 2025. This article included quotes from Dr. Ann Rougvie, an expert in Caenorhabditis elegans biology and principal investigator of the ORIP-supported Caenorhabditis Genetics Center. The article was reviewed by three ORIP grantees: Drs. David Hall, Nathan Schroeder, and David Sherwood. - Notice of Extension of the Expiration Date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed)
ORIP published a notice to extend the expiration date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed). RFA-OD-22-013 now expires on September 26, 2025. ORIP’s intent with this funding opportunity is to support resource-related research projects that are aimed at developing and characterizing new resources; improving existing resources; or acquiring deep understanding of a model system to improve the utilization, accessibility, and translational values of models to the research community. - Cryopreservation Workshop, Session V: Long-Term Preservation Methods for Nonhuman Primate Models in Biomedical Research
ORIP hosted the Cryopreservation and Other Preservation Approaches for Animal Models Workshop to address topics related to cryopreservation and other preservation methods. Session V, held on July 15, 2025, focused on long-term preservation of nonhuman primate models for biomedical research. This session brought together experts in the field to discuss current state-of-the-art techniques, as well as challenges and barriers in the field. A summary of the workshop will be posted on the ORIP website. - Wonderous Worms: Unearthing New Insights Into Health
NIH News in Health published an article titled “Wonderous Worms: Unearthing New Insights Into Health” in July 2025. This article included quotes from Dr. Ann Rougvie, an expert in Caenorhabditis elegans biology and principal investigator of the ORIP-supported Caenorhabditis Genetics Center. The article was reviewed by three ORIP grantees: Drs. David Hall, Nathan Schroeder, and David Sherwood. - Notice of Extension of the Expiration Date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed)
ORIP published a notice to extend the expiration date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed). RFA-OD-22-013 now expires on September 26, 2025. ORIP’s intent with this funding opportunity is to support resource-related research projects that are aimed at developing and characterizing new resources; improving existing resources; or acquiring deep understanding of a model system to improve the utilization, accessibility, and translational values of models to the research community. - International Mouse Phenotyping Consortium–Knockout Mouse Phenotyping Project Annual Fall Meeting
The International Mouse Phenotyping Consortium–Knockout Mouse Phenotyping Project (KOMP) Annual Fall Meeting was held on September 15–16, 2024. An ORIP staff member monitored overall project progress and exchange of scientific knowledge of the international collaboration, contributed to the discussions, conducted an in-depth review of the data provided, and crafted meeting conclusions. The meeting conclusions were communicated to the NIH KOMP Working Group and ORIP and DPCPSI leadership. - Czech Centre for Phenogenomics Conference 2024
An ORIP staff member represented the International Mouse Phenotyping Consortium–Knockout Mouse Phenotyping Project at an international community phenotyping conference on September 17–18, 2024. He participated in discussions regarding the use of animal models for the development of preclinical drug testing pipelines, as well as genome editing therapeutics. - ORIP Concept Clearance (Reissue): National Primate Research Centers Program
In light of the National Primate Research Centers (NPRCs) Program’s demonstrated success and the critical need to ensure national availability of nonhuman primate (NHP) resources, ORIP requested concept clearance from the Council of Councils on September 12, 2024, to continue its support for the program. The NPRCs Program complements and enables the missions of the other NIH institutes and centers by providing the animals, facilities, expertise, and resources required to enable NHP research in specific disease areas. - Cryopreservation Workshop Session II: Cryopreservation and Development of Sustainable Germplasm Repositories for Aquatic Biomedical Models
The second session of the Cryopreservation and Other Preservation Approaches for Animal Models Workshop was held on September 9–10, 2024. Session II focused on the advancements and future needs of genetic resources of aquatic biomedical models, including zebrafish, Xenopus, Ambystoma, and Xiphophorus. The meeting featured three keynote talks and panel presentations by more than 36 panelists. The workshop participants discussed challenges associated with funding and training, the need for standardized protocols, and the benefits that universal data management systems and training hubs would provide.
ORIP-Supported Research Highlights
- Vinculin Y822 Phosphorylation Regulates Adhesion Remodeling During Cardiomyocyte Maturation
Mechanical forces play a vital role in regulating cell function. Mechanosensitive proteins are molecules on and within the cell that are needed to sense mechanical stimuli. Defects in the ability to sense and convert mechanical stimuli into biochemical signals within a cell are involved in the development of such diseases as asthma, cancer, and cardiomyopathy. In the heart, cell–matrix and cell–cell adhesions adjust in response to increased cardiac demand and growth, which are mechanical stimuli of the heart. Vinculin (VCL) is a mechanosensitive protein found in the heart that links the protein actin to cell–matrix and cell–cell adhesions. Using heart cell culture and mouse models (both sexes used), researchers studied how VCL regulates changes in these interactions. Results showed that phosphorylation of the amino acid pY822 in VCL regulates these adhesion interactions in the heart. This highlights the importance of post-translational modifications of proteins in heart function. - Conditional Dmd Ablation in Muscle and Brain Causes Profound Effects on Muscle Function and Neurobehavior
People with Duchenne muscular dystrophy (DMD) have skeletal and cardiopulmonary weakness caused by changes to the dystrophin protein, and up to one-third also are diagnosed on the autism spectrum. Researchers created an improved mouse model that allowed them to remove large gene isoforms (mRNA variations of the gene that may alter function) within the coding for dystrophin. The mouse Dmd gene has several isoforms that affect the skeletal muscle, heart, and brain. Researchers were able to define tissue-specific requirements of dystrophin in skeletal muscle during early and postnatal muscle growth and regeneration. They also observed some learning, cognitive, and social deficits in this 4- to-6-month-old male mouse model that are shared by other DMD mouse models. This increased understanding of how dystrophin loss affects people with DMD will help researchers develop gene therapies and treatment strategies. - Exceptional Diversity of Allorecognition Receptors in a Nonvertebrate Chordate Reveals Principles of Innate Allelic Discrimination
Allorecognition—the ability to distinguish self from non-self—is found in many species and is the basis for many processes, such as mate choice, space competition, and immune function. Botryllus schlosseri is a marine invertebrate (a life form lacking a spine) that has many similarities to vertebrates in allorecognition genomic organization and signaling pathways. Researchers used B. schlosseri to investigate allorecognition and identified an unprecedented level of receptor diversity and adaptive ability in the alleles (alternative versions of a gene) used to determine compatibility. These results provide insight into signal processing and allorecognition processes across a broad range of animals. - A Tandem Repeat Atlas for the Genome of Inbred Mouse Strains: A Genetic Variation Resource
Tandem repeats (TRs) are repetitive DNA sequences. TRs are a significant source of genetic variation in the human population, responsible for unique biomedical traits among individuals and more than 60 genetic diseases. Researchers used long-read sequencing and state-of-the-art computational programs to produce a database of more than 2 million TRs that cover 39 inbred mouse strains (males used). Results showed that there were important similarities and differences among species and that TR alleles (alternative versions of a gene) are important for genetic discovery. Analysis of two biomedical phenotypes (physical characteristics), which were characterized in inbred mouse strains more than 40 years ago, identified the genetic factors that can cause these phenotypes. This research is essential for characterizing the unique genetic variations that cause trait differences and advancing fundamental biological research and translational medicine. - A Porcine Model of Fanconi Anemia
Fanconi anemia (FA) causes birth and developmental defects because of disrupted DNA repair. Without the ability to repair DNA damage, mutations continue to collect in the patient’s tissues, which leads to anemia, bone marrow failure, and cancer. Mouse and rat models for FA do not mimic the key clinical symptoms of FA, such as anemia. A pig model of FA could accurately mimic many of the clinical features seen in human patients because pigs have similar physiology and a relatively long lifespan. Researchers targeted the FANCA gene in domestic pigs. The FANCA porcine model (sex not stated) showed skeletal abnormalities, extreme sensitivity to agents that cause DNA crosslinks (a type of DNA damage), hematopoietic progenitor cell reduction, enlarged red blood cells, and reduced neutrophil (a type of immune cell) numbers in peripheral blood. Mitomycin C treatment resulted in a tenfold increase in chromosomal radials—where a segment of one chromosome breaks off and attaches to another, causing unbalanced rearrangements due to improper DNA repair—which is a diagnostic marker for FA in patients. This study shows that the FANCA porcine model is a promising preclinical model for developing strategies to prevent bone marrow failure and malignancies in FA patients. - Long-Acting Lenacapavir Acts as an Effective Preexposure Prophylaxis in a SHIV Challenge Macaque Model
Preexposure prophylaxis (PrEP) is a form of medicine that protects a person from getting a disease rather than having to treat them after they get sick. Daily oral PrEP is an effective way to prevent new HIV infections, but it must be taken as instructed. PrEP that requires less-frequent doses would make it easier and more convenient to keep taking the medication and would reduce clinical visits. Using 3- to 5-year-old male rhesus macaques, researchers showed that a single dose of lenacapavir injected beneath the skin produced sustained levels of the drug in plasma. It also provided strong preventive activity against a high-dose simian-human immunodeficiency virus (SHIV) administered rectally. No drug resistance emerged, and SHIV infections occurred only when the drug level fell below the target needed for complete protection. These findings give researchers critical data about dosing intervals, protective concentrations, and the long-acting potential of lenacapavir. This knowledge will support lenacapavir’s progression to human HIV PrEP trials. - Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge with Simian-Tropic HIV
Lenacapavir is a U.S. Food and Drug Administration–approved drug for treating multidrug-resistant HIV and needs to be taken only twice a year. Preexposure prophylaxis (PrEP) is a form of medicine that protects a person from getting sick rather than having to treat them after they get a disease. Because lenacapavir shows long-acting drug activity, it may be an ideal candidate for PrEP, as current PrEP medications require daily dosing. Researchers used experiments in vitro (in the lab, outside of a living organism) to show that lenacapavir has strong antiviral activity. Using 4- to 9-year-old male pigtail macaques (PTMs), researchers showed that a single dose of lenacapavir injected beneath the skin protected the PTMs from simian-tropic HIV-1 virus. After 419 days, researchers depleted T cell (a type of immune cell) levels in the PTMs and showed that low-level viral infections did not emerge. This study supports the evidence for moving lenacapavir into human PrEP development. - A Thymus-Independent Artificial Organoid System Supports Complete Thymopoiesis from Rhesus Macaque–Derived Hematopoietic Stem and Progenitor Cells
The creation of T cells (specialized blood cells protecting the body from infections and diseases) involves many steps that begin with T cell progenitor cells (cells that become T cells) in the bone marrow. T cells finish developing and multiply in the thymus. Although nonhuman primates (NHPs) serve as key models for studying T cell development and output under normal and disease conditions, no non-animal technology for T cell development and output currently exists. To address this gap, researchers developed a rhesus macaque (RM)–specific organoid (3D cell cultures that contain several cell types and mimic specific functions of an organ). This NHP organoid mimics thymopoiesis (a series of events leading to the creation of T cells) in a thymus-tissue-free environment. This study is the first to demonstrate an NHP-specific artificial thymic organoid that models thymopoiesis and can be used in future research studies to understand T cell development and output in different diseases. - In Utero Rescue of Neurological Dysfunction in a Mouse Model of Wiedemann-Steiner Syndrome
Wiedemann-Steiner syndrome (WDSTS) is a rare, autosomal-dominant (only one mutated gene copy is needed for symptoms to develop) genetic disorder that causes intellectual disability, abnormal facial features, and reduced growth. WDSTS occurs when the histone lysine methyltransferase 2A (KMT2A) protein is mutated. In previous studies using mouse models, syndromes related to WDSTS, such as Rett and Kabuki, have shown promise in being treatable after birth. The researchers created a mouse model for WDSTS (both sexes included) and showed that the genetic disorder could be treated in the womb by restoring KMT2A protein function. This model could be used in future studies to identify possible therapies and the window for treatment. - Alternating Hemiplegia of Childhood Associated Mutations in Atp1a3 Reveal Diverse Neurological Alterations in Mice
Pathogenic variants (changes in a gene that increase a person’s risk of developing a genetic disorder) in the Na+/K+ ATPase transmembrane ion transporter (ATP1A3) gene cause a spectrum of neurological disorders, including alternating hemiplegia of childhood (AHC). In patients, about 65% of AHC cases are caused by one of two specific mutations. Mouse models that mimic these mutations are limited by early death, which hinders our understanding of the molecular and cellular mechanisms that drive AHC. The researchers used a hybrid approach to create mouse models for these two most common ATP1A3 variations that did not suffer from early death. The researchers characterized the mouse models (both sexes included) and found that the two ATP1A3 variations cause different disease symptoms, including motor function impacts, behavior changes, and the inflammation of nervous system tissue. These mouse models can be used to test possible therapies for AHC. - Long-Acting Lenacapavir Acts as an Effective Preexposure Prophylaxis in a Rectal SHIV Challenge Macaque Model
Nonhuman primate (NHP) studies were essential in advancing lenacapavir as a long-acting HIV prevention agent. In this rhesus macaque study with male animals, a single subcutaneous dose of lenacapavir produced sustained plasma concentrations and showed strong prophylactic activity against high-dose simian-human immunodeficiency virus (SHIV) rectal challenge. Animals whose lenacapavir levels exceeded the clinically relevant target experienced complete protection, establishing a clear exposure–efficacy relationship. Breakthrough infections occurred only when drug levels declined below this threshold, and no resistance emerged, further validating the model. These findings provided critical translational evidence for dosing intervals, protective concentrations, and the long-acting potential of lenacapavir, directly supporting its progression into human HIV pre-exposure prophylaxis trials. - Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge with Simian-Tropic HIV
In this preclinical study, a single subcutaneous dose of lenacapavir conferred complete protection in a pigtail macaque (PTM) model (males only) against a high-dose intravenous challenge with a simian-tropic HIV-1 virus, which carries the HIV-1 capsid. Lenacapavir showed potent in vitro activity against the virus and displayed sustained plasma exposure in vivo after injection. All vehicle-control animals became infected, whereas the lenacapavir-treated cohort remained uninfected. The model confirmed that PTM exposure levels were relevant to human dosing and reinforced the translational rationale for moving lenacapavir into human pre-exposure prophylaxis development. - Preclinical Macaque Studies Underpinning the Development of Long-Acting Lenacapavir
The 2024 Breakthrough of the Year named by Science was the drug lenacapavir, which is used as pre-exposure prophylaxis (PrEP) to reduce HIV infection. Nonhuman primate models played a central role in establishing lenacapavir’s potential as a long-acting HIV prevention agent. Across studies using both SHIV and simian-tropic HIV-1 (stHIV-A19), single subcutaneous doses of lenacapavir generated sustained plasma levels and consistently protected male rhesus and pigtail macaques from high-dose mucosal or intravenous viral challenge. These models defined the exposure–efficacy relationship by showing complete protection whenever lenacapavir concentrations exceeded clinically relevant thresholds, while breakthrough infections occurred only when drug levels fell below those targets. Importantly, no lenacapavir-associated resistance emerged in infected animals. The macaque data also confirmed that protective exposures were aligned with achievable human pharmacokinetics, strengthening the translational bridge to clinical dosing strategies. These two studies provided essential evidence that long-acting lenacapavir could deliver durable prophylactic protection, directly supporting its advancement into human HIV PrEP clinical trials. - Polyploidy Promotes Transformation of Epithelial Cells into Nonprofessional Phagocytes
Removing dead and damaged cells is important for keeping organisms healthy. Under stressful conditions, such as food scarcity, infection, or temperature changes, unnecessary cells can be removed to save energy and maintain balance. Phagocytes are immune cells that remove invading microbes, foreign material, and damaged or dead cells. Specific cells like macrophages act as phagocytes, but other cells, called nonprofessional phagocytes (NPPs), also can take on this role if needed. NPPs need to change from an immature to mature state and undergo activation before they can clear dead and damaged cells. However, the molecular and cell pathways that cause the transitions and activation of NPPs are not well understood. Researchers used fruit flies to study the transition and activation of NPPs. They found that in fruit flies, certain cells in the ovaries can become NPPs capable of removing dead cells during egg development, which is triggered by a signaling pathway called Notch. This process involves the cells multiplying their chromosome sets to more than two, a cell state called polyploidy. Then, the polyploid cells activate JNK signaling, which helps them engulf and remove the dead cells. This research suggests the importance of polyploidy for NPPs to function properly and maintain health during stress. - Phage-Displayed Synthetic Library and Screening Platform for Nanobody Discovery
Nanobodies are tiny, stable antibodies (a protein that binds to a specific antigen and helps the immune system destroy it) from camels that are valuable in research and medicine. Traditionally, creating nanobodies requires immunizing camels, which is expensive and time consuming. In this study, researchers described the development of a high-throughput screening method for nanobodies using a synthetic library displayed on phages (viruses that infect bacteria). They tested this method by screening for nanobodies that target various secreted proteins found in fruit flies. The identified nanobodies worked well for applications like immunostaining (labeling a specific protein in a sample on a microscope slide) and immunoblotting (a technique that measures the amount of protein in a sample using an antibody). The synthetic library used in this study is now available for nonprofit use, facilitating the development of high-quality nanobodies for biomedical research and therapeutic development. - PLAA/UFD-3 Regulates P-bodies Through Its Intrinsic Disordered Domain
Maintaining protein balance in cells is essential for survival and adapting to new environments in all species. In eukaryotes (organisms that have a membrane-bound nucleus, from yeast to humans), this balance is controlled through different stages, such as making proteins, modifying them, and breaking them down. The phospholipase A2 activating protein (PLAA) is a protein found in all eukaryotes that helps sort and degrade proteins through interactions with other molecules. However, its exact targets and interactions are not well understood. Researchers studied PLAA in nematode worms and discovered it has a unique role in cellular processing bodies, called P-bodies, that process cytoplasmic mRNA (molecules that carry the genetic information to make proteins). PLAA interacts with another protein, DCAP-1, which helps process mRNA. This study suggests that PLAA forms a complex with DCAP-1 to regulate protein balance in two ways: breaking down proteins and managing mRNA in P-bodies. - Estimating Realized Relatedness in Free-Ranging Macaques by Inferring Identity-by-Descent Segments
Biological relatedness is a key consideration in studies of behavior, population structure, and trait evolution. Except for parent–offspring dyads (pairs), pedigrees (diagrams that show family member relationships) do not capture individual relatedness perfectly. The number and length of identity-by-descent (IBD) segments of DNA yield the most precise estimates of being related. The researchers used different methods to estimate IBD segments in free-ranging rhesus macaques (both sexes included). Then, they compared the IBD-based estimates to current methods, such as pedigree. The results show that IBD-based estimates are more reliable and provide more detailed information about relations. Future population studies can use this accurate method to investigate predictors and consequences of being genetically related. - Structural and Functional Basis of Mechanosensitive TMEM63 Channelopathies
Mechanotransduction occurs when cells sense changes in outside physical forces and convert them into electrical or chemical signals. To complete this process, certain ion channels, such as transmembrane protein 63A (TMEM63A), are used to pass ions and fats across cell membranes. TMEM63B and TMEM63C are part of the same protein family as TMEM63A. Mutations in these three channels cause neurodevelopmental disorders. Researchers identified the changes in protein structure and function for common TMEM63A and TMEM63B mutations. The results provide insight into TMEM63 channel dysfunction. - In Vivo Prime Editing Rescues Alternating Hemiplegia of Childhood in Mice
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disease that can cause involuntary muscle contractions, low muscle tone, paralysis on one side of the body, abnormal eye movements, seizures, and intellectual disability. There currently is no treatment. AHC is caused by a mutation in the gene ATP1A3; three variations of the ATP1A3 gene mutation are responsible for 65% of cases. Researchers used prime editing and base editing tools to correct ATP1A3 gene mutations in cells isolated from AHC patients and two mouse models for AHC (sex not specified). Results showed that physical characteristics of AHC were corrected and that treated mice had an extended lifespan. These findings support the potential use of prime editing and base editing tools to treat this neurological disease. - Determinants of Successful AAV-Vectored Delivery of HIV-1 bNAbs in Early Life
More than 100,000 children are infected with HIV each year through vertical (mother-to-child) transmission. Antiretroviral treatment lapses can occur during postpartum care, which then increases levels of HIV in the mother, resulting in an increased risk of transmission to the infant through breastfeeding. Broadly neutralizing antibodies (bNAbs) defend the host from pathogens and have shown potential as a safe therapy for infants. Gene transfer using adeno-associated virus (AAV) offers an opportunity to provide preventive care for infants at risk of getting HIV. Researchers used an infant rhesus macaque model (sex not specified) for simian immunodeficiency virus (SIV)—equivalent to HIV but in nonhuman primates—to determine whether a single intramuscular injection of AAV-bNAb could protect against SIV vertical transmission. The therapy was more effective in newborn rhesus macaques than in older infants and juveniles, and the newborns also were less likely to develop anti-drug antibodies. Results showed that functional antibodies were present even after 4 years. These findings support the possible use of AAV-bNAb to protect infants from contracting HIV. - Multiplexed Proteomic Biosensor Platform for Label-Free Real-Time Simultaneous Kinetic Screening of Thousands of Protein Interactions
Existing methods for producing functional protein libraries are costly and time-consuming, and they lack real-time kinetic (protein interaction) screening abilities. Researchers developed an automated platform for high-throughput production and screening of a library of proteins on biosensor surfaces. Biosensors are devices that can bind a specific protein in a sample containing many proteins to generate a measurable signal unique to the protein of interest. This allows researchers to complete large-scale kinetic measurements for drug discovery, biomarker identification, and diagnostic development. The platform created by the researchers is known as the Sensor-Integrated Proteome On Chip (SPOC®). SPOC uses nanowells to capture 2,400 proteins at the same time on a single gold biosensor chip. The SPOC biosensor chip can then be analyzed with different techniques to generate kinetic data. The SPOC will allow researchers to understand protein interactions on a large scale for research and clinical applications. - miR-33 Inhibition as a Novel Therapeutic Approach for Treating Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a devastating disorder caused by changes in the dystrophin gene sequence, which results in the absence of a functional dystrophin protein. Several microRNAs (a type of RNA that can bind to other molecules) can alter DMD by changing gene expression. In this review article, the authors discuss inhibiting microRNAs as a new therapy for DMD. Researchers have shown in a DMD mouse model (sex not specified) that blocking miR-33a/b, a microRNA, can improve muscle regeneration (regrowth of damaged tissue) and reduce DMD symptoms. Anti-microRNA oligonucleotides (AMOs) are short chains of DNA or RNA that block microRNAs. Injection of an AMO that blocks miR-33a/b in the DMD mouse model improved muscle regrowth and increased gene pathways involved in muscle regrowth. These studies highlight the impact of microRNA signaling pathways in DMD and show how they could serve as targets for new therapies to treat the disease. - Distinguishing PEX2 and PEX16 Gene Variant Severity for Mild, Severe, and Atypical Peroxisome Biogenesis Disorders
Peroxisomes are structures in cells that play an important role in metabolism and chemical changes of complex fats. Peroxisomal biogenesis disorders (PBDs) are caused by mutations in peroxin (PEX) genes. PBDs are autosomal recessive diseases—a mutated PEX gene must be passed down from both parents. In patients, symptoms of PBD range from mild to severe multi-organ system defects depending on gene mutations and even different mutations in the same gene. Researchers wanted to understand how different mutations cause the variation in symptoms seen in patients. In fruit flies, the researchers replaced the fly Pex genes with two human PEX genes—PEX2 and PEX16—and different mutant forms of these genes. Researchers found that some mutations caused severe symptoms, such as seizure-like behavior, while others were milder. Introducing a normal functional copy of the human PEX genes into the flies with mutant Pex genes alleviated the symptoms. Further studies with fruit flies will help us understand how different PEX gene mutations affect PBD severity in patients. - Functional Analysis of Pathogenic Variants in LAMB1-Related Leukoencephalopathy Reveals Genotype–Phenotype Correlations and Suggests Its Role in Glial Cells
Cells are surrounded by a matrix, known as the basement membrane, that provides structural support and enhances signaling. Laminin B1 (LAMB1) is a matrix protein in the basement membrane that helps form this supportive structure around cells. Mutations (mistakes in the DNA sequence) in the LAMB1 gene can cause rare neurological disorders. Researchers studied the fruit fly version of the LAMB1 gene, which is LanB1. Using fruit flies, the researchers were able to gain insight into the link between LAMB1 gene mutations and disease symptoms. The LanB1 protein is found in a subset of brain cells, called glia cells, and in the blood–brain barrier. Reducing the amount of LanB1 protein in the blood–brain barrier caused shorter lifespans and movement defects in the fruit flies. Human LAMB1 was not functional in flies, but fly experiments showed that some LanB1 mutations cause severe defects, while others were milder. Tests in human cells suggested some LAMB1 mutations might cause disorders, even in the presence of a normal copy of LAMB1. This study reveals the role of LanB1 in keeping the healthy structure of the fly blood–brain barrier and understanding the consequences of different LAMB1 mutations in humans. - SIV Proviruses Seeded Later in Infection Are Harbored in Short-Lived CD4+ T Cells
HIV can stay dormant for years by mixing its genetic materials into immune cells, making it difficult to remove. It remains unclear which HIV-infected cells survive long term. This study used samples from simian immunodeficiency virus (SIV)–infected macaques (sex not specified) to examine how and when virus-infected cells become part of the long-lived reservoir. Researchers discovered that newer viral sequences were found in short-lived CD4+ T cells, and long-lived cells contained older, more genetically varied viruses. These results suggest that viruses from early infection persist in the long term, whereas newer infections remain in cells that die off quickly, providing insights on future HIV treatment strategies. - Transplantation of Human Kidney Organoids Elicited a Robust Allogeneic Response in a Humanized Mouse Model
Kidney organoids are helping advance studies focused on kidney diseases. However, the use of kidney organoids in studies on tissue transplanted from one organism into another is not well explored. Researchers used a humanized mouse model (sex not specified) that contained a human immune system. Following the transplantation of kidney organoids into the humanized mice, researchers looked at the immune response at days 20 and 30. Results showed that transplantation of kidney organoids caused infiltration of immune cells and an increase in the number of T cells. This study provides a novel platform for bridging the gap between mouse and human studies, which may hasten the development of drugs that reduce tissue rejection in organ transplants. - Caspase-11 Drives Macrophage Hyperinflammation in Models of Polg-Related Mitochondrial Disease
Mitochondria are the energy-producing organelles within cells. Mitochondrial diseases lead to chronic health impairments, which can be worsened by environmental exposures, including bacterial infections. Researchers used a mouse model (sex not specified) to study polymerase gamma (Polg)–related mitochondrial disease. They found that infection with the bacteria Pseudomonas aeruginosa causes macrophages (a type of immune cell) to have an increased response. The response happens through cytokine-mediated increases of caspase-11 and guanylate-binding proteins, which leads to lung inflammation. These findings will help scientists find targets to develop therapies to limit infection- and inflammation-related complications in mitochondrial diseases. - Synaptic Dysregulation in a Mouse Model of GRIN2D Developmental and Epileptic Encephalopathy
Researchers studied a mutation in the GRIN2D gene that is linked to severe developmental delays and epilepsy in children. Using a mouse model (both sexes used), researchers showed that the mutation caused early-onset seizures, abnormal brain activity, and learning impairments. Functional analysis demonstrated increased synaptic activity, leading to heightened hippocampal excitability. These findings highlight how this mutation alters excitatory and inhibitory neuronal signaling in the brain. This work suggests that precision genetic therapy is a promising treatment strategy for patients with mutations in the GRIN2D gene. - Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Mutation Reduces Endothelial TDP-43 and Causes Blood–Brain Barrier Defects
Mutations in the TARDBP gene are linked to neurodegenerative diseases, such as familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study showed that the protein TDP-43 is reduced in brain endothelial cells of male and female mice with this mutation—leading to blood–brain barrier (BBB) disruption and causing inflammation, protein buildup, and cognitive issues—mimicking key features of neurodegeneration. These findings suggest that endothelial TDP-43 loss contributes directly to BBB breakdown and disease pathology in ALS-FTD.
Progress on Priority 2: Modern Physical Infrastructure to Accelerate Research Discoveries in Human Health and Diseases
Programs and Activities Highlights
- Fiscal Year 2025 C06 Post-Award Webinar
On November 20, 2025, ORIP held an informational webinar to kick off fiscal year 2025 NIH C06 construction projects. More than 75 participants from all 14 grantee institutions attended, representing various project roles, including principal investigators, signing officials, project managers, and architect/engineering team members. The webinar covered such key topics as project and budget timelines, design requirements, technical review processes, environmental policy, NIH grant compliance, and reporting requirements throughout the grant period and 10-year duration of Federal Interest following project completion. ORIP’s Division of Construction and Instruments supports programs that fund the construction, renovation, and modernization of research space by issuing notices of funding opportunities when congressional appropriations are available. The overall objective of these programs is to provide modernized physical infrastructure that meets up-to-date engineering requirements to conduct cutting-edge NIH-funded biomedical research. - Closeout Site Visit to the University of Miami
On December 18, 2025, ORIP staff conducted a virtual site visit to the University of Miami (UM) Miller School of Medicine’s centralized biospecimen repository facility, supported by NIH grant C06OD030170. Opened in January 2025, this facility has expanded storage capacity from 500,000 to 5 million specimens, featuring automated −80°C modular storage with triple-redundant backup systems and continuous monitoring to ensure sample integrity. Advanced capabilities include biological safety cabinets, cryogenic storage, and dedicated clinical trials infrastructure supporting NIH-funded research, multisite collaborations, and precision medicine initiatives with electronic medical record integration. The facility has managed 1.2 million samples across 222 studies, serving 68 principal investigators from 17 UM departments and 11 external partners. This infrastructure strengthens UM’s competitiveness for NIH funding and faculty recruitment while advancing the UM Precision Medicine Initiative (UPROMISE) in Alzheimer’s disease, cancer, cardiovascular disease, neurological disorders, and infectious diseases research, with regional impact on the broad biomedical research field. - Closeout Site Visit to the University of Louisville
On January 16, 2026, ORIP staff conducted a virtual closeout site visit to the University of Louisville’s newly renovated centralized vivarium, supported by NIH construction grant C06OD030129. The $8 million award funded the transformation of the ninth floor of the A-Tower Research Building into a modern, centralized vivarium and research facility. The project consolidated animal housing previously dispersed across nine A-Tower floors and a dental school space, significantly improving operational efficiency and research workflows. The new facility features a highly flexible design with multipurpose rooms that can function as housing or procedural space. Key enhancements include improved barrier-level biosecurity, isolation of the vivarium from public areas, animal biosafety level 2 procedure space, specialized inhalation rooms, and expanded zebrafish housing capacity. Occupancy of the facility began on December 12, 2024, and the facility now supports 29 investigators from 12 departments and four centers with more than $34 million in NIH funding, positioning the institution for future research growth. - Final Site Visit to the University of Illinois Chicago
On July 14, 2025, ORIP staff performed a virtual site visit to two NIH-funded facilities at The University of Illinois Chicago that were supported by grants C06RR016560 and C06RR020087. The Center for Structural Biology building met all objectives, providing state-of-the-art nuclear magnetic resonance spectrometry, electron microscopy, and mass spectrometry cores that now serve more than 225 internal and 130 external users. Expanded instrumentation, increased user demand, and improved environmental sustainability have driven significant growth, including major increases in core revenue, multiple patents, startup companies, and federally supported drug discovery efforts. The Behavioral Neurobiology Center renovation modernized outdated laboratories and created integrated basic and clinical neuroscience research spaces. The facility enabled substantial faculty and trainee recruitment, approximately $60 million in grant funding, and hundreds of neuroscience publications. Shared spaces promote translational research in addiction, depression, and resilience. - Final Site Visit to the University of Michigan
The virtual site visit on July 11, 2025, reviewed two NIH-funded facilities at the University of Michigan (UM) that were supported by grants C06RR017514 and C06RR016573. Renovation of the Pharmacy Research Building created shared laboratories for the Center for Molecular Drug Targeting, enabling major growth in research productivity, recruitment of eight faculty members, support for 325 trainees, $79 million in funding, 634 publications, 47 patents, and several UM-affiliated startup companies. These activities continue producing long-lasting impact on research and economic outcomes. The Positron Emission Tomography Cyclotron Facility successfully replaced an outdated cyclotron; expanded radiochemistry capabilities; and supported extensive clinical and research programs, including U.S. Food and Drug Administration–approved radiopharmaceuticals, 479 publications, and 19 patents. The facility serves more than 30 personnel and numerous external investigators with $87 million in research funding, broadly benefiting research communities beyond the region. - Final Site Visit to The University of Alabama at Birmingham
On July 9, 2025, ORIP staff conducted a virtual site visit to The University of Alabama at Birmingham (UAB) facilities renovated under NIH grants C06RR015490, C06RR017453, and C06RR020612. The multi-phased projects modernized Volker Hall’s animal research infrastructure by expanding nonhuman primate and small-animal housing, increasing cage sanitation capacity, and creating surgical and imaging suites and staff support areas. UAB met all project objectives, resulting in increased research capability, enhanced efficiency, and improved compliance with contemporary standards. The facilities now support more than 100 animal-use protocols, over 500 users, and research projects totaling $166 million. Renovations strengthened faculty recruitment, enabled workforce development programs, and led to significant downstream outcomes. These outcomes included 30 intellectual property disclosures, 78 patent applications, and 3 startup companies. Continued investments from UAB are planned, including a new biomedical research building and additional infrastructure upgrades after federal oversight ends. - Notice of Change to the Instructions for Purpose and Scope in PAR-24-167, Utilizing Equipment to Study Environmental Extrinsic Factors and Enhance Rigor and Reproducibility of Animal Research (R24, Clinical Trials Not Allowed)
ORIP published a notice to inform potential applicants of changes to the language regarding the examples of projects that will not be supported under PAR-24-167, Utilizing Equipment to Study Environmental Extrinsic Factors and Enhance Rigor and Reproducibility of Animal Research (R24, Clinical Trials Not Allowed). ORIP supports the acquisition or update of modern equipment for measuring, monitoring, recording, and reporting environmental, biological, or biobehavioral variables. - Site Visit: Purdue University
ORIP conducted a virtual site visit to Purdue University on June 20, 2025. NIH funded grant C06RR015480 for the renovation of offices and laboratories on the second, third, fourth, and fifth floors of the Robert Heine Pharmacy Building at Purdue University. Supported research areas include molecular pharmacology, medicinal chemistry, chemical biology, proteomics, development of inhalation products of antimicrobials, and pharmaceutical protein biotechnology. - Site Visit: University of New Mexico
ORIP conducted a virtual site visit to the University of New Mexico (UNM) on June 20, 2025. NIH funded grant C06RR017566 for the construction of a multimodal neuroimaging facility for animal research on neurological and psychiatric disorders at UNM’s Health Sciences Center (HSC). C06RR016492 supported the renovation of the second floor of the new multidisciplinary research facility for the Toxicology and Environmental Diseases program in the College of Pharmacy at UNM HSC. C06RR018888 funded the construction of the neurobiology building to support the clinical and translational research programs of the psychiatry and neurology departments at UNM HSC. - Site Visit: SUNY Stony Brook
ORIP conducted a virtual site visit to the State University of New York (SUNY) Stony Brook on May 2, 2025. ORIP manages NIH extramural construction programs that fund the construction, renovation, and modernization of research spaces. Grant C06RR029841 provided funding for the construction of the first Animal Biosafety Level 3 Laboratory in the Division of Laboratory Animal Resources at the SUNY Stony Brook Health Sciences Center. Grant C06RR014510 funded the renovation of 25,443 square feet of space on the third floor of the Life Sciences Building at SUNY Stony Brook to create research space for an interdepartmental molecular and cellular biology research group focused on yeast. - Site Visit: Medical University of South Carolina
ORIP conducted a virtual site visit to the Medical University of South Carolina (MUSC) on June 16, 2025. Grant C06RR018823 provided funding to outfit two floors of shell space in the new Darby Children’s Research Institute (CRI) building at MUSC. Renovated research laboratories supported multi-departmental, interdisciplinary research programs in developmental neuroscience and cardiovascular developmental biology and cutting-edge core facilities in lipidomics, cell sorting, tissue engineering, and histology. Grant C06RR015455 funded the upgrade of the sanitization and related support facilities in the existing animal facility on the seventh floor of the Basic Science Building at MUSC and the outfitting of the adjoining shell space on the seventh floor of the CRI into a rodent barrier facility.
ORIP-Supported Research Highlights
- Therapeutic Remodeling of the Ceramide Backbone Prevents Kidney Injury
Acute kidney injury (AKI) can be caused by a broad range of conditions, including drug toxicity, sepsis, preexisting kidney disorders, and heart failure. AKI increases a person’s chance for chronic kidney disease, morbidity, and mortality, but an effective therapy for AKI is not currently available. Proximal tubules (PTs) within the kidney secrete nonfiltered substances while reabsorbing filtered molecules. Abnormal lipid metabolism and lipid imbalances are linked to AKI, but the underlying mechanisms remain unknown. Using previously published data, urine samples from patients, and 8- to 11-week-old male mouse models, researchers showed that AKI triggers the production of toxic ceramides in PTs and that urine ceramide levels correlate with disease severity. Ceramides disrupt mitochondrial structure and function by altering critical protein complexes, and damage requires a specific molecular feature of ceramides created by the DES1 enzyme. Genetic deletion of DES1 protected mice from kidney injury following bilateral ischemia reperfusion. A novel DES1 inhibitor provided a protective effect, offering a promising therapeutic strategy. This work reveals ceramide remodeling as a promising target for treating AKI. - Gastrointestinal MAIT Cells in Chronic HIV-1 Infection
Mucosa-associated invariant T (MAIT) cells are innate-like T cells abundant in blood and the gastrointestinal tract. They help control infections by producing immunoproteins, killing infected cells, and hindering microbial growth. Chronic HIV infection reduces MAIT cells and increases vulnerability to secondary infections. In this work, researchers studied immunological responses of blood and mucosal MAIT cells to microbes between people (both sexes) with chronic HIV who are on long-term antiretroviral therapy and people without HIV. While MAIT cells were depleted in the blood of HIV-infected individuals, mucosal MAIT cell levels remained comparable between the two groups. Blood MAIT cells responded robustly to general immune stimulation. However, mucosal MAIT cells responded poorly to Escherichia coli bacterial stimulation, suggesting selective unresponsiveness to normal microbes while maintaining immune functions to other stimuli. HIV-infected individuals showed an impaired MAIT cell antimicrobial defense, providing novel insights worth studying. - Metabolomic Profiling and Characterization of a Novel 3D Culture System for Studying Chondrocyte Mechanotransduction
Osteoarthritis (OA) is a chronic degenerative joint disease that affects more than 37% of people over age 60. The pericellular matrix (PCM), the microenvironment that directly surrounds each cartilage cell, plays an important role in mechanotransduction. This process allows cells to sense changes in outside physical forces and convert them into electrical signals and cartilage functions. Using a novel 3D culture system equipped with cyclical compression and loading stimulation to mimic physiological conditions, researchers studied human and bovine cartilage cell mechanotransduction under different cell culture conditions. Metabolomic profiling—a way of observing all chemical changes within a cell that produces compounds and energy for biological processes—showed unique changes and strong PCM development as indicated by the production of both collagens VI and II, suggesting the 3D culture system replicates the native PCM and physiological stiffness of cartilage. By providing a physiologically relevant 3D model, future studies can look into OA pathways, cartilage tissue engineering, and novel therapies. - Deep Learning Approaches for Classifying Children With and Without Autism Spectrum Disorder Using Inertial Measurement Unit Hand Tracking Data: Comparative Study
Studies show that 50% to 88% of children with autism spectrum disorder (ASD) have differences in movement control. Researchers used an inertial measurement unit (IMU), an electronic device that measures aspects of the body, to track arm movements in 41 children (both sexes) with and without an ASD diagnosis during a hand–eye coordination task. The IMU data were used in multiple deep learning models, and the best model was retrained and reevaluated, resulting in an accuracy of 91.87% and an F1-score (a performance metric for deep learning models) of 93.66%. The study showed that different physical movement patterns in children with ASD can be identified by analyzing hand–eye coordination skills and suggested that small-scale deep learning models have the potential to help diagnose ASD. - Development and Validation of an Ultra–High Performance Liquid Chromatography–Tandem Mass Spectrometry Method for Quantifying Lenacapavir Plasma Concentrations: Application to Therapeutic Monitoring
Antiretroviral therapy (ART) is used to treat patients with HIV. Lenacapavir is a U.S. Food and Drug Administration–approved ART. Following initial doses of lenacapavir taken orally and injected beneath the skin, the patient gives themselves a dose by injection once every 6 months. With this long-acting and infrequent dosing, patients may need to be monitored to ensure that proper drug levels are achieved in the body to prevent viral mutations that could cause drug resistance. Researchers developed a novel mass spectrometry (an analytical chemistry instrument to measure molecules in a sample) method to test the effectiveness of ART by measuring lenacapavir levels in human plasma. The researchers validated the new method using a large range of clinically relevant doses. The results showed that the method is precise and consistent. This study suggests that the method can monitor lenacapavir levels in human plasma and evaluate ART effectiveness in clinical settings. - Cryo-EM Structures of HBV Capsids from Human Cells at Near-Atomic Resolution
More than 800,000 deaths per year are caused by hepatitis B virus (HBV)–induced liver inflammation, cirrhosis (scarring liver), and hepatocellular carcinoma. Cryogenic electron microscopy (cryo-EM) is a microscope technique that images samples cooled to very low temperatures. Using cryo-EM, researchers determined the structure of HBV capsids (a protein shell that surrounds and protects the virus) purified from human cells. Along with computer simulations and analyses, results highlighted the dynamic regulation of HBV capsid structure and how it contributes to virion (an infectious form of virus) secretion, viral assembly, and envelopment. This could be a potential mechanism for developing HBV-specific antiviral drugs for disease treatment. - Targeting FSP1 Triggers Ferroptosis in Lung Cancer
Growing evidence shows that cancer cells are highly sensitive to lipid peroxidation (a chemical process that degrades lipids in cell membranes). Ferroptosis is a form of cell death that relies on iron and lipid peroxidation, and two proteins known to suppress ferroptosis are GPX4 and FSP1. In this study, researchers used 8- to 12-week-old genetically engineered mouse models for lung cancer (both sexes used) and selectively deleted these two proteins. Results showed that deleting GPX4 and FSP1 triggered lipid peroxidation and significantly inhibited lung adenocarcinoma tumor development. FSP1 was essential for protecting tumors from ferroptosis in vivo (within an organism) but not in vitro (outside of an organism), highlighting the utility of the mouse models to mimic the physiological conditions of patients. FSP1 expression correlated with disease progression and reduced survival in lung adenocarcinoma patients, unlike GPX4. Drug inhibition of FSP1 showed substantial therapeutic efficacy in preclinical models. These findings establish ferroptosis as a barrier to tumor development and identify FSP1 inhibition as a promising novel therapy for lung cancer patients. - Imaging-Guided Deep Tissue In Vivo Sound Printing
Three-dimensional printing has shown promise for patient-specific implants and therapies but often requires invasive surgical procedures. This study introduces a novel platform called deep tissue in vivo sound printing (DISP), which uses injected ultrasound-responsive “bioinks” to fabricate complex bioprints deep within living tissues on demand. With ultrasound imaging offering precise targeting and real-time monitoring, DISP achieved high-resolution (~150 µm) and high-speed (up to 40 mm s-1) printing of functional biomaterials—including conductive hydrogels, cell-laden constructs, drug-loaded carriers, and bioadhesives—within mouse bladder and rabbit muscle in vivo (sex not specified). Biocompatibility was confirmed via histology, showing no signs of toxicity or adverse immune response. DISP offers promise for personalized implants, targeted drug delivery, and in situ bioelectronics and may revolutionize regenerative therapy for broad biomedical applications. - Targeting SUMOylation Promotes cBAF Complex Stabilization and Disruption of the SS18::SSX Transcriptome in Synovial Sarcoma
Metastatic synovial sarcoma (SS) is an aggressive and incurable soft tissue sarcoma in children and young adults. Using human SS cell lines and genetically engineered mouse SS models (males only), researchers identified that SS models are significantly sensitive to genetic targeting of the SUMOylation pathway, which appears to affect chromatin structure and transcriptional function. The SS18::SSX fusion oncogene in SS elevates several SUMO pathway genes. Furthermore, subasumstat, a small-molecule SUMOylation inhibitor, leads to stabilization of the cBAF complex on chromatin and a shift away from the SS18::SSX-driven transcriptome, inducing DNA damage, cell death, and tumor inhibition. These results suggest SUMOylation as a therapeutic target in SS, inviting clinical evaluation of SUMO-pathway inhibitors in the treatment of this aggressive disease. - Reprogramming Neuroblastoma by Diet-Enhanced Polyamine Depletion
Neuroblastoma, a highly lethal childhood cancer, is characterized by hyperactive MYC signaling and depends on local polyamine levels. Difluoromethylornithine (DFMO) was recently approved by the U.S. Food and Drug Administration for treatment of children with high-risk neuroblastoma, and combined treatment studies could improve therapeutic efficacy. DFMO inhibits the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase. This study in female mice demonstrates that combining a ProArg-free diet with DFMO dramatically reduces tumor polyamine levels. RNA sequencing, ribosome profiling, and proteomics analysis revealed that the combined treatment triggers ribosome stalling at codons ending in adenosine, shifts translation from proliferation genes to differentiation proteome, and markedly prolongs survival. This work suggests that diet and pharmacology can be used to target metabolic-translation coupling for treatment of neuroblastoma. - Development and Validation of an Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Quantifying Lenacapavir Plasma Concentrations: Application to Therapeutic Monitoring
Patients with multidrug-resistant HIV-1 infection are at increased risk for progression to AIDS, hospitalization, and death. Thus, clinicians must verify consistently adequate lenacapavir exposure over the dosing interval. In this study, the investigators developed and validated a novel mass spectrometry method to assess the effectiveness of antiretroviral therapy (ART) by quantifying lenacapavir concentrations in blank human plasma (sex not specified). With infrequent dosing of the first-in-class long-acting HIV-1 capsid inhibitor, ensuring adequate lenacapavir concentrations will be important, particularly to the treatment-experienced people living with HIV. By validating the assay design over a large, clinically relevant dosing range, the results revealed the fast, ultra-high-performance method achieved high precision and repeatability, suggesting that the new method can be used to monitor lenacapavir concentrations in human plasma and practically assess ART efficacy in clinical settings. -
SIV Infection Induces Alterations in Gene Expression and Loss of Interneurons in Rhesus Macaque Frontal Cortex During Early Systemic Infection
HIV infection affects the central nervous system and is associated with neurological symptoms. In this study, researchers reported that acute simian immunodeficiency virus (SIV) exposure triggers rapid, cell type–specific neurobiological injury in male and female rhesus macaques. Thousands of differentially expressed genes indicated strong interferon-driven immune activation at 10 days and enduring downregulation of neuronal pathways at 20 days. These findings suggest early interneuron loss and disrupted signaling may initiate long-term HIV-associated neurocognitive disorder (HAND). Overall, this study provides insight into the neuropathology of acute SIV infection and may inform new approaches for treating HAND.SIV Infection Induces Alterations in Gene Expression and Loss of Interneurons in Rhesus Macaque Frontal Cortex During Early Systemic Infection
HIV infection affects the central nervous system and is associated with neurological symptoms. In this study, researchers reported that acute simian immunodeficiency virus (SIV) exposure triggers rapid, cell type–specific neurobiological injury in male and female rhesus macaques. Thousands of differentially expressed genes indicated strong interferon-driven immune activation at 10 days and enduring downregulation of neuronal pathways at 20 days. These findings suggest early interneuron loss and disrupted signaling may initiate long-term HIV-associated neurocognitive disorder (HAND). Overall, this study provides insight into the neuropathology of acute SIV infection and may inform new approaches for treating HAND. - Computational Design of Sequence-Specific DNA-Binding Proteins
The investigators used computational modeling to design small proteins that recognize specific DNA sequences. They first generated a library of small proteins that could bind to the backbone of DNA and further refined this library to account for specific differences in base pairs; then they used iterative rounds of sequence optimization to design the final protein. These protein–DNA structures were then crystallized. The researchers compared the computational models with the crystal structures and reported excellent agreement. These DNA-binding proteins were then tested in cells, showing that they are capable of either suppressing or activating transcription. This in silico custom DNA design method showed potential applications in gene regulation and editing. - Programmable Protein Ligation on Cell Surfaces
The unique protein dynamics on the cell surface are often altered with disease. Researchers developed a synthetic biology system called SMART (splicing-modulated actuation upon recognition of targets) that can distinguish these cell surface features. They demonstrated that SMART allowed a controlled “decoration” of cells with diverse proteins—including enzymes, fluorescent reporters, and binding domains—without requiring harsh chemicals or disrupting cell viability. This highly selective method works across multiple cell types and maintains the biological activity of both the surface protein and the attached payload. This system may offer applications for future studies that involve cell engineering, as well as mechanistic studies of cell-surface signaling and interactions. - Magnetically Labelled iPSC-Derived Extracellular Vesicles Enable MRI/MPI-Guided Regenerative Therapy for Myocardial Infarction
Stem cell–based therapies have shown promise for treating heart diseases, which are a leading cause of death and a global public health burden. Researchers used stem cell–derived extracellular vesicles (EVs) filled with superparamagnetic iron oxide (SPEVs) as imaging contrast agents for imaging-guided regenerative treatment of heart attacks. While manipulating and imaging EVs is challenging in a clinical setting, the researchers were able to detect these new SPEVs using magnetic resonance imaging and magnetic particle tracking imaging in female mice. They showed that both native EVs and their engineered SPEVs significantly improved cardiac function and dramatically decreased scar size. The study demonstrated that the engineered SPEVs offer a novel, cell-free approach for cardiovascular regenerative medicine with both noninvasive imaging-tracking capabilities and therapeutic benefits for heart repair. - Distinct CD8+ T Cell Dynamics Associate with Response to Neoadjuvant Cancer Immunotherapies
Recent advances in monoclonal antibodies have transformed cancer treatments, but more work is needed to predict responses to immune checkpoint inhibitors (ICIs) (treatments that help the immune system recognize and attack cancer cells). In this study, researchers tested combinations of three ICIs—anti-PD-1 (nivolumab; Nivo) alone, nivolumab plus CTLA-4 (ipilimumab; Ipi), and nivolumab plus LAG-3 (relatlimab; Rela)—in a cohort of patients (both sexes included) with head and neck squamous cell carcinoma (NCT04080804). They found that the two combination therapies may enable higher pathologic response rates than nivolumab alone. These combination regimens target specific CD8+ T-cell states within the tumor microenvironment. Nivo+Rela, but not Nivo+Ipi, induces widespread T-cell receptor sharing among transcriptional states, as well as T-cell receptor diversity in patients who respond to therapy. This work may provide biomarkers that could play a crucial role in tailoring therapies to patient profiles. - Integrative Multi-Omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes in Ovarian Cancer
Ovarian cancer is the deadliest gynecologic cancer, and effective, long-lasting treatments are needed to maintain a good quality of life for patients with recurrent disease. Researchers conducted a phase 2 clinical trial (NCT02853318) to assess the efficacy of combining pembrolizumab, bevacizumab, and oral cyclophosphamide to treat recurrent ovarian cancer in 40 patients (sex not specified). Their results indicated that the combination regimen extended the patient progression-free survival compared with the single-drug therapies alone. The combination therapy improved quality of life, increased rates of disease control, induced more favorable microbial patterns, and enhanced amino acid and lipid metabolism. These clinical results provide additional treatment options for women with recurrent ovarian cancer. - Lysosomal Dysfunction and Inflammatory Sterol Metabolism in Pulmonary Arterial Hypertension
Dysregulation of lysosomal activity and cholesterol metabolism causes inflammation, but the relevance of these functions to pulmonary arterial hypertension (PAH) is unclear. Researchers examined this topic using both human (both sexes included) and male rodent (rats and mice) endothelial cells (ECs). They found that nuclear receptor coactivator 7 (NCOA7) functions as a homeostatic brake and prevents oxysterol-induced inflammation, EC dysfunction, and PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism, which alters endothelial immunoactivation and correlates with mortality in humans. This study links fundamental lysosomal biology and oxysterol metabolism to EC behavior and may guide potential molecular diagnostics and therapeutics in PAH. - Genetic QT Score as a Predictor of Sudden Cardiac Death in Participants with Sleep-Disordered Breathing in the UK Biobank
Obstructive sleep apnea is characterized by repetitive upper airway collapse. Patients with obstructive sleep apnea have prolonged corrected QT (QTc) intervals during the daytime, which is linked to increased risk for ventricular arrhythmias, sudden cardiac death (SCD), and all-cause mortality. The goal of this study was to evaluate the association between a polygenic risk score for QT prolongation (QTc-PRS), QTc intervals, and mortality in male and female patients enrolled in the UK Biobank. The researchers found that the QTc-PRS was associated with SCD among participants with sleep apnea but not among those without sleep apnea. This work suggests that sleep apnea is a significant modifier of genetic risk. Additionally, Black participants with sleep apnea had a particularly high risk of SCD. - The Saponin Monophosphoryl Lipid A Nanoparticle Adjuvant Induces Dose-Dependent HIV Vaccine Responses in Nonhuman Primates
Researchers tested an HIV vaccine booster using an adjuvant (an ingredient that helps vaccines work better) called saponin monophosphoryl lipid A nanoparticle (SMNP). Using male and female nonhuman primates, researchers found that higher doses of SMNP triggered stronger immune responses, including robust B-cell activation and the production of two neutralizing antibodies (important for long-lasting protection). Only high-dose groups showed significant levels of these antibodies. Findings highlight the importance of dose-dependent potency of vaccines in shaping immune responses. This study suggests SMNP’s potential for use in humans as a next-generation vaccine. - Inferring Drug–Gene Relationships in Cancer Using Literature-Augmented Large Language Models
Scientific literature contains a wealth of information on cancer and cancer drugs. Researchers developed GeneRxGPT, a large language model (LLM)–powered tool that analyzes biomedical literature to uncover drug–gene relationships for cancer treatment. By integrating PubMed data and advanced LLMs, this tool overcomes limitations of static LLMs (e.g., outdated knowledge, misleading results). A case study in liver cancer, supported by an ORIP S10–funded computing cluster, showed a key link between a particular set of mutations and sensitivity to the cancer drug sorafenib, pointing to a new treatment strategy. Designed for accessibility, GeneRxGPT is a promising resource to accelerate cancer drug discovery by helping researchers explore drug–gene interactions. - Engineered Epithelial Curvature Controls Paneth Cell Localization in Intestinal Organoids
Intestinal organoids, laboratory-grown mini-organs that model the intestine, are emerging as a new complementary approach in research. Researchers have developed a new method to design the architecture of intestinal organoids by engineering the curvature of their tissue. Using an ORIP-funded photomanipulation and imaging system combined with a light-sensitive hydrogel, researchers precisely controlled the width and depth of intestinal organoids, mimicking the natural intestinal folds in humans. This structure guided the placement of Paneth cells, which are key to gut health and immunity. By improving the consistency of cell organization, this approach enhances the reproducibility and functionality of organoid models, making them more useful for studying diseases, testing drugs, and advancing restorative medicine. - Giant Polyketide Synthase Enzymes in the Biosynthesis of Giant Marine Polyether Toxins
Researchers identified the “PKZILLAs,” massive polyketide synthase genes in the harmful algae Prymnesium parvum that are responsible for producing prymnesins—large polyether toxins linked to fish kills. PKZILLA-1 and PKZILLA-2 encode enormous proteins, each with more than 90 enzyme domains, producing precursors to A-type and B-type prymnesins. This discovery unveils the long-mysterious biosynthesis of these toxins, providing insights into the genetic and enzymatic mechanisms behind polyether production. It challenges previous size expectations in biological systems, offering new perspectives on polyketide biosynthesis. - Noninvasive Targeted Modulation of Pain Circuits With Focused Ultrasonic Waves
This study explores noninvasive modulation of the anterior cingulate cortex using low-intensity transcranial-focused ultrasound to treat chronic pain. In a randomized crossover trial with 20 male and female patients, 60% experienced significant pain reduction immediately after active stimulation, with sustained effects on days 1 and 7, compared with minimal improvements with sham stimulation. Pain was reduced by 60% immediately post-stimulation and by 43% and 33% on days 1 and 7, respectively. The approach was well tolerated, with only mild, temporary side effects, highlighting its potential as a noninvasive alternative to brain surgery for pain management.
Progress on Priority 3: Innovative Cross-Disciplinary Research Training in Model Systems for Human Health and Diseases
Programs and Activities Highlights
- Specialized Research Training in Animal Models and Related Resources: Focus Group, Session 1
ORIP held a series of focus groups involving veterinary trainees, early-career scientists, mentors, and training program directors to identify and cultivate opportunities for collaborations and partnerships that address challenges and synergize strategies and resources supporting recruitment and retention of veterinary scientists. In the first session, held April 11, 2025, selected training program directors and mentors in the ORIP T32 program were invited to discuss the challenges and opportunities that exist in the current program. - K01 Special Emphasis Research Career Award (SERCA) Guidelines
In April 2025, ORIP updated its K01 SERCA guidelines with new language covering updated ORIP priorities, including new approach methodologies (NAMs) for complementing animal research relevant to human health and diseases. The SERCA is intended to stimulate the development of veterinary scientists with interests in comparative medicine and related research questions. - ORIP and National Eye Institute Training Programs
Training Program Directors from ORIP and the National Eye Institute met on September 16, 2024, to compare their training program outcomes and future strategies. ORIP's Division of Comparative Medicine offers career development support for individuals with D.V.M. or Ph.D. degrees, as well as predoctoral veterinary students.
ORIP-Supported Research Highlights
- Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages
Macrophages are a type of immune cell that are highly plastic—meaning environmental cues change their phenotype (physical characteristics) and behavior. Cancer cells take advantage of this plasticity to recruit and create tumor-associated macrophages (TAMs) that benefit the tumor microenvironment and promote tumor development. However, the underlying mechanism that cancer cells use to recruit TAMs remains unknown. In this study, researchers used murine and human non-small cell lung cancer cell models to show that integrin αvβ3 expression is needed to drive TAM accumulation. This research highlights a novel mechanism—αvβ3-mediated glutamine secretion—to promote TAM accumulation and begin tumor development. Developing therapies that target this signaling axis could help treat αvβ3-expressing cancers. - Apparent Expansion of Virulent Vibrio parahaemolyticus in Humans and Sea Otters
Vibriosis, caused by Vibrio species, causes about 80,000 human cases of illness in the United States each year. It is considered the most important public health threat from seafood consumption and marine recreational activities. In addition, pathogenic (disease-causing) Vibrio species infect marine animals, including otters. Although sea otters could be used as a marine bioindicator, virulence (ability of the bacteria to cause disease) factor data on Vibrio species that infect northern and southern sea otters are limited. Researchers used genomic epidemiology data to identify virulence factors of Vibrio species collected from different sources in the United States. Virulence factor prevalence varied depending on whether the isolate was environmental or derived from an organism. Specific virulence factors in V. parahaemolyticus were most prevalent in humans and northern sea otters. Co-occurrence of T3SS2 and T6SS1, two virulence factors, was linked to disease findings. This study highlights that V. parahaemolyticus undergoes selection pressures that result in the expansion of virulent strains that infect humans and sea otters. - Inducing Ferroptosis to Impede Metastasis by Inhibiting the Calcium Channel TRPC6
Aggressive cancers such as triple negative breast cancer (TNBC) are able to resist standard chemotherapy and metastasize (spread to other parts of the body) quickly. Previous research shows that the calcium channel TRPC6 helps a subset of cancer cells remain quiescent (a reversable, inactive cell state), which promotes chemotherapy and ferroptosis resistance. Researchers noted that circulating tumor cells isolated from breast cancer patients displayed a higher level of TRPC6 than the primary tumor. Using in vitro (outside of an organism) experiments and 6- and 12-week-old female mice, researchers studied whether the quiescent subset of TNBC cells was sensitive to ferroptosis when targeting TRPC6. Results showed that TRPC6 can cause ferroptosis resistance. The underlying mechanism for ferroptosis resistance was that TRPC6 limits c-Myc to sustain high levels of glutathione. TNBC metastasis was significantly reduced when a TRPC6 inhibitor was used. This study supports a possible opportunity to mitigate TNBC metastasis by targeting TRPC6. - Dual Chitosan Hydrogel and Polylactic Acid Microparticle Delivery System Reduces Staphylococcal Osteomyelitis and Soft Tissue Infection
The bacteria Staphylococcus aureus is a common cause of the bone infection osteomyelitis (OM). Biofilms are a community of bacteria within a matrix that grows on surfaces and is hard to treat with antibiotics. This biofilm-forming bacterial infection is treated with long-term, high-dose antibiotics. However, this extended use of antibiotics can cause organ damage and promote antibiotic resistance (meaning the drug is no longer effective in treating the bacterial infection). Developing biomaterials (naturally derived or engineered substances for medical use in the body) for localized antibiotic delivery is key to avoiding these negative outcomes. Researchers used polylactic acid microparticles in antimicrobial chitosan hydrogel (CH PLA), both loaded with fosfomycin antibiotic, to combat S. aureus infection. Using 13-week-old female CD rats, researchers showed that CH PLA reduced S. aureus infection. Local treatment of OM using CH PLA decreased the bone defect area and the amounts of bacteria present in the bone and soft tissue. CH PLA is a promising biomaterial that may be an effective alternative to long-term antibiotic use to prevent S. aureus–mediated OM. - Identification of Antibodies to Chondrocyte and Synoviocyte Antigens in Equine Osteoarthritis
Approximately 33 million people in the United States suffer from osteoarthritis (OA), and the rate has doubled in the past 30 years. The immune processes that drive OA development are not well understood. Past rheumatoid arthritis studies have shown that antibodies (proteins that bind to a specific molecule and help the immune system destroy it) will target molecules on living cells in a patient’s body. OA is common in horses, which makes them a relevant model for studying the condition. To understand whether antibodies target live cells in joints, causing OA to worsen, researchers used 2- to 18-year-old horses (both sexes used). Blood and synovial fluid samples contained antibodies that target live cells—chondrocytes and synoviocytes—in the joint, and antibody concentrations were correlated with OA severity. This research will help inform future studies on antibody production and therapies to target immune pathways in OA. - Assessing Gut Microbial Provisioning of Essential Amino Acids to Host in a Mouse Model with Reconstituted Gut Microbiomes
Gut microbes produce many metabolites which are substances made when the body processes food into energy and materials for cells. Metabolites include fatty acids and essential amino acids (EAAs), and they can affect the host’s health. EAAs are vital for making proteins and are involved in many cellular functions. A major challenge in microbiome research is showing the function of gut microbes in hosts, such as how microbe-derived EAAs affect the host. Using 3-week-old female germ-free mice and mice with a restored gut microbiome, researchers showed that gut microbes did not contribute to host EAA pools across the brain, kidney, liver, and muscle tissues. This study highlights the need for more research on the functional restoration of gut microbes and the importance of analytical techniques when trying to understand microbial nutrients. - Macrophage-Engaging IgG4 Antibody Triggers Cytotoxicity Against Integrin αvβ3+ Cancers
Integrins are cell receptors that span the cell membrane and play an important role in signaling pathways—including survival and movement. Integrin αvβ3 is absent in most normal cells and is a biomarker of cancers that form in the epithelial tissue, lining most organs and body surfaces. Integrin αvβ3 also is a driver of tumor stemness (properties of cancer cells that promote tumor development) and drug resistance in epithelial cancers, which makes it an ideal target for therapy. Tumor-associated macrophages (TAMs) are immune cells that are abundant in the epithelial cancer microenvironment, but they reduce the efficacy of an antibody therapy that targets cells with integrin αvβ3. Using in vitro (outside of the body) cultures and 8- to 10-week-old female mice, researchers revealed an antibody-mediated therapy that activates the anti-tumor activities of TAMs to overcome drug-resistant, integrin αvβ3-positive epithelial cancer. This study supports the use of antibody-based therapies to activate immune cells and destroy the tumor. - Inhalable Hsa-miR-30a-3p Liposomes Attenuate Pulmonary Fibrosis
The extracellular matrix is a substance that surrounds the cells to provide structural support and enhance signaling. Idiopathic pulmonary fibrosis (IPF) is an incurable type of lung disease in which too much extracellular matrix is deposited in the lungs. Current treatments for IPF only manage symptoms or slow disease progression. Liposomes, which are fat-like particles that can be created to contain drugs or other substances, may serve as a therapy for IPF. Inhalable hsa-miR-30a-3p-loaded liposomes (miR-30a) were studied as potential treatments for pulmonary fibrosis in 6-week-old male mice. Previous studies have found that exosomes (cellular packages that allow molecules to be passed from one cell to another) with therapeutic effects on pulmonary fibrosis are enriched in these liposomes. The researchers showed that inhaled miR-30a reduced some effects of IPF and improved lung function. - Cooked Broccoli Alters Cecal Microbiota and Impacts Microbial Metabolism of Glucoraphanin in Lean and Obese Mice
Brassica vegetables, such as broccoli, are a unique source of compounds known as glucosinolates (GSLs). The protein myrosinase turns GSLs into isothiocyanates (ITCs). ITCs are bioactive compounds that display many health benefits and reduce the risk of certain cancers, degenerative diseases, cardiovascular disease, and inflammation. Cooking broccoli deactivates the myrosinase found in the vegetable, so our body relies on bacteria-derived myrosinase to convert GSLs into ITCs. The gut microbiome differs between lean and obese populations, and differences in the gut microbiome can hinder the conversion of GSLs to ITCs. The researchers studied the impact of cooked broccoli on cecal (a part of the large intestine) microbial conversion of glucoraphanin (GRP), the most abundant GSL of broccoli, in 16-week-old lean and obese male mice. The findings suggest that eating cooked broccoli enhances microbial GRP conversion and produces more bioactive ITCs. Eating cooked broccoli also changed the cecal microbiome composition and increased the abundance of several types of bacteria. This study can inform future strategies that focus on changing microbial pathways that break down GSLs to promote health in different populations of people. - Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity
Millions of cancer patients and cancer survivors face an increased risk of developing cardiotoxicity and cardiovascular (system encompassing the heart and blood vessels) dysfunction because of cancer progression and cancer treatments. Irregular autophagy causes this increased risk. Autophagy is the breakdown of old, damaged, or abnormal proteins within the cell that are then recycled for use in other proteins. Managing autophagy could protect the cardiovascular system during cancer treatment. This review notes the advances in regulating autophagy and how it could be applied to treat cardiotoxicity while improving cancer treatment outcomes. The researchers highlight in vitro (outside a living organism) models and other tests that are needed to obtain findings that can allow autophagy therapies to be translated into the clinic. - A STAT3/Integrin Axis Accelerates Pancreatic Cancer Initiation and Progression
In pancreatic ductal adenocarcinoma (PDAC), inflammation and cell stress within the environment surrounding the tumor are known to promote cancer cell growth and increase drug resistance. The signal transducer and activator of transcription 3 (STAT3) pathway directs these responses. Researchers used human cancer cells and mouse models for PDAC (both sexes included) to identify binding sites of STAT3 that regulate gene expression and are linked to poor survival. The results showed that STAT3 interacts with integrin beta 3 to start and grow PDAC tumors. STAT3 also targets 18 genes that are involved in adaptive responses and can be used to identify different survival outcomes. This study highlights a new way to classify PDAC subpopulations for STAT3-targeted therapies. - Cross-species Protection Suggests Entamoeba histolytica Trogocytosis Enables Complement Resistance Through the Transfer of Negative Regulators of Complement Activation
Amoebae are single-cell organisms that can be parasites to the human body. Entamoeba histolytica, a type of amoeba, causes diarrheal disease when it invades the intestine. E. histolytica spreads through the body using the bloodstream and can evade the immune system. Amoebae eat parts of human cells—an event known as trogocytosis—which allows them to display human proteins and resist being broken down by serum in the blood. Researchers wanted to identify how amoebae resist being broken down. Results showed that amoebae display host proteins that suppress the complement pathway of the immune system, which protects them from being broken down. Other microbes can perform trogocytosis of human cells, so understanding this method of resistance could be relevant to other infections. - Loss of Hepatocyte-Specific RECK Exacerbates Metabolic Dysfunction–Associated Steatohepatitis
Metabolic dysfunction–associated steatohepatitis (MASH) is a serious liver disease resulting from excess fat buildup. MASH is a major health crisis worldwide due to increases in obesity and insulin resistance, and it is a leading cause for liver transplants in the Western world. The current approach for MASH treatment involves lifestyle changes. Therefore, identifying new ways to treat MASH is critical. Reversion Inducing Cysteine Rich Protein with Kazal Motifs (RECK) is a molecule that regulates the extracellular matrix (ECM). The ECM surrounds a cell, provides structural support, and enhances signaling. The role of RECK in metabolic liver disease is poorly understood. The researchers showed in a previous study that RECK gain-of-function (increased amounts above normal) in liver cells protected mice against diet-induced MASH. In this study, researchers used two mouse models (sex not specified) that depleted RECK in liver cells. They showed that the lack of RECK significantly increased inflammation, cell swelling, and fibrosis (too much ECM). These studies highlight RECK’s potential as a novel therapy for MASH. - Remdesivir Postexposure Prophylaxis Limits Measles-Induced “Immune Amnesia” and Measles Antibody Responses in Macaques
Measles is a highly contagious viral disease that is a leading cause of childhood illness and death around the world. The measles virus (MeV) replicates considerably in tissue where immune cells are produced and activated. MeV causes the immune system to lose circulating antibodies (a protein that binds to a specific antigen and helps the immune system destroy it) against other pathogens, which leaves the infected child susceptible to other infectious diseases. Researchers wanted to determine whether remdesivir, a broad-spectrum antiviral (a drug that affects a wide range of viruses), can hinder MeV-induced loss of antibodies to other pathogens. They measured antibody reactivity using a MeV rhesus macaque model (both sexes included). Remdesivir given 3–14 days after MeV infection limited the loss of antibodies to non-MeV pathogens. Remdesivir also reduced the immune system’s ability to mount an antibody response to MeV. This study shows that early treatment of measles with remdesivir prevents the loss of antibodies against other pathogens but lessens the response to MeV. - Microbiome and Metabolome Association Network Analysis Identifies Clostridium_sensu_stricto_1 as a Stronger Keystone Genus Candidate Than Bifidobacterium in the Gut of Common Marmosets
The common marmoset is a nonhuman primate model for the microbiome (the collection of microorganisms found in the body) studies. Previous studies have shown significant variation in the gut microbiome among individual common marmosets due to such factors as diet, age, sex, and captivity. Researchers identified how the gut microbiome and metabolome (the collection of molecules made or used during the chemical processes of a cell) change over time, using fecal samples collected from 1- to 9-year-old healthy marmosets of both sexes. Results showed that certain bacteria have a stronger influence within the gut than others. Bifidobacterium was the most abundant genus (a higher level of classification than species) of bacteria and the driver of microbiome differences among individual marmosets. Also, the results suggest that Bacteroidales bacteria compete with Bifidobacterium for resources within the gut. The researchers created a Keystone Candidate Score to identify the most influential bacteria, which were Clostridium_sensu_stricto_1 and Alloprevotella. This study provides insight into how the microbiome—including interactions among different bacteria and competition for resources—affects the health of common marmosets. - Acute Degradation of Nucleolin Reveals Its Novel Functions in Cell Cycle Progression and Cell Division in Triple Negative Breast Cancer
The nucleolus is a vital compartment within the cell where ribosomes (which link amino acids together to form proteins) are assembled. Traditional experimental methods cannot deplete nucleolar proteins (proteins that make up the nucleolus) while keeping the cell alive, which limits our understanding of the biological functions of these proteins. Researchers used two advanced techniques to successfully deplete and identify the biological functions of nucleolin (NCL) in triple-negative breast cancer (TNBC) cells. NCL is one of the most abundant nucleolar proteins in the body. Results showed that depleting NCL in TNBC cells causes defects in cytokinesis, a step in cell division. Defects in cell division result in a smaller increase in TNBC cell numbers. Cancer therapies that target cellular mitosis (the process of a single cell dividing into two new cells) were more useful when NCL was degraded. This research supports a new role for NCL in TNBC cell division and reveals that inhibiting NCL may enhance cancer therapies. - Dia–B–Ties: B Cells in the Islet–Immune–Cell Interface in T1D
Roughly 30 million people worldwide suffer from type 1 diabetes (T1D). T1D is an autoimmune disease that requires lifelong use of insulin. A key feature of T1D is T-cell-driven damage of insulin-producing β islet cells in the pancreas. This review discusses the role of B lymphocytes (an immune cell) in T1D disease development and progression. B lymphocytes are an essential mediator of communication between other immune cell types and islet cells in what is known as the islet–immune interface. B lymphocytes coordinate communication among different cell types through antigen (a substance that tells your immune system whether something is harmful) presentation, cytokine secretion, and antibody production. Using these methods, B lymphocytes activate autoreactive (an antibody that targets a normal molecule within a person) T cells that target islet cells, which amplifies inflammation in the pancreas during the initial stages of T1D development. The review outlines current and potential therapies that target B lymphocytes. These therapies potentially could be beneficial in T1D treatment. - Epidemiologically Relevant Phthalate Mixture and Mono(2-Ethyl-5-Hydroxyhexyl) Phthalate Exposure Alter Cell Energy Metabolism in Primary Mouse Granulosa Cells
Many products—including plastic food containers, medical tubing, children’s toys, and personal care products—contain phthalate diesters. Phthalates leach from plastics and negatively affect the environment and female reproductive system. In women, phthalate exposure is linked to endometriosis, polycystic ovarian syndrome, and reduced fertility. The molecular pathways by which phthalate exposure affects ovaries remain understudied. Researchers tested the effects of different phthalate exposures on granulosa cells (cells that support egg cell development). Using female mouse granulosa cells, the researchers found that short-term exposure to phthalates altered the expression of specific genes, Ldha and Glut1, and affected the ability to create energy. These data indicate that phthalate exposure alters metabolism in granulosa cells. - Sphingosine-1-Phosphate Signaling Mediates Shedding of Measles Virus–Infected Respiratory Epithelial Cells
Measles virus (MeV) is an infectious respiratory virus that has a significant global impact and is a major cause of childhood mortality. A single infected person can transmit MeV to nearly 20 other people. Respiratory epithelial cells (cells that line the respiratory system) are the target of MeV infection, and shedding these cells into airborne droplets allows transmission to other people. Researchers used epithelial cells isolated from the tracheas of rhesus macaques (sex not specified) to understand the mechanisms underlying how MeV-infected epithelial cells are shed. Results showed that sphingosine-1-phosphate (S1P) signaling plays a key role in cell shedding. Inhibiting S1P signaling delayed MeV-infected epithelial shedding and increased the amount of virus in the epithelial lining. These findings demonstrate the key role of host cellular responses in MeV infection - A Potential Role for c-MYC in the Regulation of Meibocyte Cell Stress
The integrated stress response (ISR) controls cell survival and promotes apoptosis (a type of cell death) through the protein CHOP during prolonged or severe stress. The ISR has not been evaluated in cancers originating in the glands of the eyelid, such as ocular adnexal sebaceous carcinoma (SebCA). Although SebCA is uncommon, mortality rates of up to 40% have been reported. Researchers studied the role of MYC in regulating the ISR in human meibomian gland epithelial cells (HMGECs) located in the eyelid. Results showed that inhibiting MYC in HMGECs stimulates the ISR, results in a smaller increase in the number of cells, and promotes apoptosis. These data support the role of high MYC as an underlying mechanism for SebCA tumorigenesis. - Activated Polyreactive B Cells Are Clonally Expanded in Autoantibody Positive and Patients with Recent-Onset Type 1 Diabetes
Patients who are prediabetic do not have symptoms but do have autoantibodies (cells that target a normal molecule in the body) present. However, it remains largely unknown how autoreactive B cells affect the development of Type 1 diabetes (T1D). Researchers isolated B cells from the blood of patients with T1D, patients who were prediabetic (AAB), and relatives who were not diabetic and not autoreactive. Results showed that B cells from AAB and T1D patients have altered gene expression in cell signaling and inflammation pathways. These results provide a foundation for future studies focused on identifying biomarkers or creating cell-targeted treatments for T1D. - From In Vitro Development to Accessible Luminal Interface of Neonatal Bovine-Derived Intestinal Organoids
Diarrhea caused by infectious agents in the intestine of newborns remains a major human health concern. Three-dimensional (3D) culture techniques of intestinal epithelial cells have been developed to study host–pathogen interactions as new approach methodologies (NAMs) that complement animal research. With these methods, primary intestinal stem cells from donor intestinal crypts are cultured within an extracellular matrix, which supports the self-organization of the multipotent cells into 3D structures known as intestinal organoids. In this study, the team developed intestinal organoids and organoid-derived single-layer cell cultures to enable research on early-life intestinal function and disease. These organoids captured key aspects of the gastrointestinal lining, how it functions, and the unique roles of different cell types. These models replicate the in vivo intestinal epithelium through their multicellularity, self-replication, and differentiation into mature epithelial cell types and provide a complementary platform for studying human health and disease. - Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines
Prostate cancer (PCa) ranks second worldwide in cancer-related mortality, but only a few animal models exhibit naturally occurring PCa that recapitulates the symptoms of the disease. Neutered dogs have an increased risk of PCa and often lack androgen receptor (AR) signaling, which is involved in upregulating tumorigenesis but can also suppress aggressive cell growth. In this study, researchers sought to understand more about the role of AR signaling in canine PCa initiation and progression by restoring AR in canine PCa cell lines and treating them with dihydrotestosterone. One cell line exhibited AR-mediated tumor suppression; one cell line showed altered proliferation (but not migration or invasion); and a third cell line exhibited AR-mediated alterations in migration and invasion (but not proliferation). The study highlights the heterogeneous nature of PCa in dogs and humans but suggests that AR signaling might have therapeutic potential under certain conditions.
Progress on Priority 4: Outreach and Awareness of ORIP Resources and Programs
Programs and Activities Highlights
- Notice of Extension of the Expiration Date for RFA-OD-23-001: Animal and Biological Material Resource Centers (P40, Clinical Trial Not Allowed)
The purpose of this notice is to extend the expiration date for RFA-OD-23-001: Animal and Biological Material Resource Centers (P40, Clinical Trial Not Allowed). Therefore, with the addition/extension by one application due date, RFA-OD-23-001 now expires on May 9, 2026. - Focus Group: Extramural Integrity Training Scenario and Case Study
An ORIP program official participated in a discussion on extramural integrity, including a breakout session, on May 20, 2025. The breakout session was intended to gather ideas for case studies, narratives, and scenarios related to extramural integrity. The goal of this effort was to compile a group of potential general extramural integrity case studies, narratives, and scenarios with transferable messaging across business areas. Focus group members consisted of NIH Staff Training Advisory Committee members, Office of Extramural Research staff, NIH institute and center officers, and training developers. - Notice of ORIP Participation in PA-25-080, NIH Support for Conferences and Scientific Meetings (Parent R13, Clinical Trial Not Allowed)
ORIP published a notice to inform potential applicants that effective immediately, the office is participating in PA-25-080, NIH Support for Conferences and Scientific Meetings (Parent R13, Clinical Trial Not Allowed). The purpose of the NIH Research Conference Grant (R13) is to support high-quality conferences that are relevant to public health and to the scientific missions of participating institutes and centers. ORIP’s high-priority thematic areas are (1) developing models for human diseases, (2) accelerating research discoveries by providing access to state-of-the-art instrumentation, and (3) training and diversifying the biomedical workforce. For models-oriented conferences and meetings, proposals to be considered must be applicable to the research interests of two or more categorical NIH institutes or centers. For training-oriented conferences and meetings, applications with a primary focus on veterinary scientists as translational researchers will receive priority for consideration. - NIH Research Festival
NIH’s Intramural Research Program hosted the annual NIH Research Festival, which highlights groundbreaking intramural science and provides an opportunity for the scientific community to share and connect. The festival took place on the NIH main campus in September 2024. ORIP presented two posters at the festival, in the category of research support services. One of the posters featured information on ORIP’s various resources (e.g., aquatic, rodent, nonhuman primate, biological materials and reagents, other comparative models). The other poster highlighted the critical infrastructure that ORIP supports through the S10 Shared Instrumentation Programs, as well as the impact that S10-supported instruments have on research across the United States. - Oklahoma Medical Research Foundation Construction Supports Inclusive Immunology Research and Proactive Initiatives
ORIP published a research highlight in August 2024 featuring the Oklahoma Medical Research Foundation (OMRF). ORIP’s Extramural Construction Programs supported renovations to facilities for research in molecular immunology and genetics, cardiovascular biology, and autoimmune diseases at OMRF. With this funding, OMRF has been able to expand the breadth of its research, recruit exceptional scientists and trainees, and foster exciting collaborations across Oklahoma and the nation. OMRF has formed partnerships with local Tribes; as a result, OMRF and Tribal clinicians were able to identify better blood markers for the Oklahoma Tribal citizens and change the way that rheumatic diseases are screened for. - S10-Funded Work Featured on Nature Genetics Cover
A recent paper, titled A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus, was featured on the cover of the July 2024 issue of Nature Genetics. This international study describes a common flanking variant that is associated with enhanced stability of repeat locus. These findings offer insight into the mechanism protecting against tandem repeat expansion, a known cause of more than 40 neurological disorders, including schizophrenia. This work received support through ORIP’s S10 shared instrumentation programs (S10OD026880 and S10OD030463) and was performed using 1,027 samples from the NIH All of Us Research Program.