Progress on Theme 3: Specialized Research Training in Animal Models and Related Resources
Programs and Activities Highlights
- 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. - Notice of Funding Opportunity Reissue (PA-24-176) and ORIP Information Update for PA-24-176
The purpose of the NIH Mentored Research Scientist Development Award (K01) is to provide support and protected time (3–5 years) for an intensive, supervised career development experience in the biomedical, behavioral, or clinical sciences leading to research independence. When NIH reissued the notice of funding opportunity, ORIP added specific information to the funding opportunity PA-24-176 in April 2024. For investigator-initiated applications submitted in response to the parent funding opportunity announcement—Mentored Research Scientist Development Award (Parent K01 – Independent Clinical Trial Not Allowed)—ORIP support is limited to graduate veterinarians (i.e., D.V.M.s, V.M.D.s, and equivalents) only. The K01 allows 4 years of protected time to develop an awardee’s research career. Once a K01 has been obtained, the awardee is permitted, and actively encouraged, to apply for additional research grants anytime during the tenure of their K award.
ORIP-Supported Research Highlights
- 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. - Controlled Stiffness of Direct-Write, Near-Field Electrospun Gelatin Fibers Generates Differences in Tenocyte Morphology and Gene Expression
Tendinopathy is associated with mobility issues, and the cell–matrix interactions involved in the development of tendinopathy are not fully understood. In this study, researchers fabricated micron-scale fibrous scaffolds that mimic native collagen fiber size and orientation. They reported that matrix metalloproteinase and proteoglycans (possible indicators of tendinopathy) were more upregulated in the presence of high-stiffness fibers than low-stiffness fibers. The authors’ findings suggest that scaffolds can serve as in vitro models for tendinopathy. Additionally, their work suggests that matrix mechanical properties contribute to cell–matrix interactions during tendinopathy formation. -
Transcriptome- and Proteome-Wide Effects of a Circular RNA Encompassing Four Early Exons of the Spinal Muscular Atrophy Genes
Spinal muscular atrophy (SMA) is a leading genetic cause of mortality in infants and often results from a deficiency of deletions of or mutations in the SMN1 gene. In this study, researchers report the transcriptome- and proteome-wide effects of overexpression of C2A 2B-3–4, a circular RNA produced by SMN1 and SMN2, in cells. They report that C2A-2B-3–4 is associated with expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation, and neuromuscular junction formation. More work is needed to investigate the role of these genes in processes associated with SMA and other pathological conditions, including cancer and male infertility.