Skip to main content

ORIP Strategic Plan 2026–2030 Progress: Archive

Progress on Priority 1|Progress on Priority 2|Progress on Priority 3|Progress on Priority 4

Progress on Priority 1: Model Resources to Advance the Study of Human Diseases

Programs and Activities Highlights

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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