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.
- T32 and T35 Directors' Consortium
A meeting of the T32 and T35 Directors’ Consortium was held on September 16, 2024. ORIP staff presented on program and grant topics to the T32/T35 directors, and NIH updates to training grant applications were discussed.
- NIH Loan Repayment Program
ORIP revised its Loan Repayment Program guidelines with new language covering updated ORIP priorities. Specifically, proposed research investigations must be applicable to the interests of two or more of the categorical NIH institutes and centers (ICs). In addition, projects that predominantly address the research interests of one NIH IC, but that are peripherally related to the research interests of other ICs, will not be considered appropriate. Extramural Loan Repayment Programs provide for the repayment of educational loan debt up to $50,000 annually for qualified health professionals performing research within the mission of NIH and supported by domestic, nonprofit, or government entities.
- Training and Career Development Resources Fact Sheet
ORIP revised its fact sheet on training and career development resources in May 2024. ORIP reviewed the fact sheet for accuracy and further clarified the Special Emphasis Research Career Award (K01). This fact sheet is one of several fact sheets that serve as valuable resources for potential investigators to learn about ORIP resources and programs.
- T32 and T35 Directors Consortium
ORIP staff facilitated a discussion on program and grant topics among the T32 and T35 directors on June 17, 2024. Topics included key changes for training grant applications, peer review, criteria for fellowship applications, and carryover requests.
Read more in the archive.
ORIP-Supported Research Highlights
- 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.
- A Review of CD4+ T Cell Differentiation and Diversity in Dogs
CD4+ T cells are an important component of both the adaptive immune response and immune maintenance. They carry out many functions and can differentiate into numerous specialized subsets, including T helper type 1 (TH1), TH2, TH9, TH17, TH22, regulatory T cells, and follicular T helper cells. CD4+ T cells also have a capacity for long-term immunological memory and rapid reactivation upon secondary exposure. However, our understanding of the role of CD4+ T cells in immune response is largely based on studies in mice, humans, and, to a lesser extent, pigs. Comparatively, our understanding of CD4+ T cells in canines is much less complete. This review summarizes the current understanding of canine CD4+ T cells from a comparative perspective by highlighting both the similarities and differences from mouse, human, and pig CD4+ T-cell biology.
- A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-Induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice
Radiation damages adipose progenitor cells and increases liver fibrosis, leading to the development of metabolic-associated fatty liver disease (MAFLD) and insulin resistance. As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize and mitigate the delayed effects of radiation exposure. Some of these effects are mediated by TGFβ pathway signaling, which increases in response to radiation exposure and causes fibrosis. In this study, IPW-5371—a small-molecule inhibitor of a TGFβ receptor called activin receptor-like kinase 5 (ALK5)—was shown to protect mice from the effects of sublethal whole-body irradiation and chronic consumption of a Western diet. Male and female mice treated with IPW-5371 exhibited lower fibrosis and fat accumulation in the liver, were more responsive to insulin, and had lower circulating triglycerides and better muscle endurance. IPW-5371 is a promising treatment for mitigating the metabolic effects of radiation exposure and preventing MAFLD.
- Cold Atmospheric Plasma Inactivates Aspergillus flavus and Fusarium keratoplasticum Biofilms and Conidia In Vitro
Fungal keratitis (FK) is a severe corneal disease associated with significant morbidity and vision loss that is caused by Aspergillus flavus and Fusarium keratoplasticum. Cold atmospheric plasma (CAP) is a novel nonpharmacologic antimicrobial intervention that has demonstrated potential as a broad-spectrum antifungal treatment. Researchers in this study assessed the efficacy of CAP against clinical FK isolates of A. flavus and F. keratoplasticum grown in vitro. CAP exhibited strong time-dependent inactivation of both fungal species, achieving complete metabolic activity inhibition within 10 minutes of treatment. These results indicate that CAP is an effective broad-spectrum antifungal and a potential treatment strategy for FK.
- Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy
A newly recognized progressive neurodegenerative disorder in Miniature American Shepherd (MAS) dogs affects gait in young adult dogs and is characterized by pelvic limb weakness and ataxia. The authors of this study used genetic analysis to map the underlying cause of the disorder, a single base-pair deletion in the ring finger protein 170 (RNF170) gene that was predicted to cause early truncation of the RNF170 protein. RNF170 variants previously were identified in human patients with spastic paraplegia-85 (SPG85) who exhibit similar clinical and pathological phenotypes to RNF170-mutant dogs. SPG85 belongs to a group of inherited neurodegenerative disorders collectively referred to as neuroaxonal dystrophy (NAD). The authors of this paper propose that RNF170-mutant MAS dogs serve as a large animal model to study underlying mechanisms and therapeutics for NAD.
- Sex-Specific Cardiac Remodeling in Aged Rats After Adolescent Chronic Stress: Associations with Endocrine and Metabolic Factors
Cardiovascular disease is a leading cause of death in the world. The potential effects of chronic stress on the development and progression of cardiovascular disease in the aged heart are unknown. In this study, researchers investigated sex- and stress-specific effects on left ventricular hypertrophy (LVH) after aging. Male and female rats were exposed to chronic stress during adolescence and then challenged with a swim test and a glucose tolerance test before and after aging 15 months. As a group, female rats showed increased LVH in response to early life stress. Male rats showed individual differences in vulnerability. These results indicate that sex and stress history can interact to determine susceptibility to cardiovascular risks.
- Evolution of the Clinical-Stage Hyperactive TcBuster Transposase as a Platform for Robust Non-Viral Production of Adoptive Cellular Therapies
In this study, the authors report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieve high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. This proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improved survival in a Burkitt lymphoma xenograft model in vivo. Their work suggests that TcB-M is a versatile, safe, efficient, and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition.
Read more in the archive.
