Programs and Activities Highlights
- 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.
- Opportunities for Veterinary Scientists at NIH
ORIP staff participated in a virtual discussion with veterinary students on opportunities for veterinary scientists at NIH, which was hosted through the University of Pennsylvania School of Veterinary Medicine on June 24, 2024.
Read more in the archive.
ORIP-Supported Research Highlights
- 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.
- Deletion of Mouse Lysyl Oxidase in Megakaryocytes Affects Bone Properties in a Sex-Dependent Manner
Lysyl oxidase (LOX) is a facilitator of extracellular matrix cross-linking, and the importance of LOX in bone formation has been addressed in both in vitro and in vivo studies. Using newly developed megakaryocyte-specific LOX knockout mice, the researchers show that LOX expressed in these scarce bone marrow cells leads to changes in bone volume and mechanical strength in male mice. No significant changes were observed, however, within the female experimental groups. The authors’ findings suggest that sex hormones could contribute to differences within these dynamics.
- Synthetic Protein Circuits for Programmable Control of Mammalian Cell Death
Natural cell death pathways have been shown to eliminate harmful cells and shape immunity. Researchers used synthetic protein-level cell death circuits, collectively termed “synpoptosis” circuits, to proteolytically regulate engineered executioner proteins and mammalian cell death. They show that the circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. This work provides a foundation for programmable control of mammalian cell death. Future studies could focus on programmable control of cell death in various contexts, including cancer, senescence, fibrosis, autoimmunity, and infection.
Read more in the archive.
