# Cellular reprogramming to promote longevity, resilience, and repair in motor unit degeneration > **NIH NIH K00** · HARVARD MEDICAL SCHOOL · 2024 · $76,273 ## Abstract PROJECT SUMMARY/ABSTRACT The global population is aging rapidly – the number of adults over 65 is expected to double by 2050. Chronological aging is an established risk factor for neurodegeneration and leads to dysfunction and loss of the motor unit (MU; a motor neuron and all the myofibers it innervates). Further, genetic variants may accelerate biological aging and acquired cellular damage in the nervous system. However, aged mammalian tissues retain an epigenetic signature, and recent publications highlight strategies such as cellular reprogramming to restore youthful tissue resilience. My long-term career goal is to obtain a tenure-track clinician-scientist position at an academic institution and establish a translational research program. Such a position will allow me to achieve my long-term scientific goal to investigate cellular aging of the nervous system in the setting of genetic predisposition. My short-term scientific goal and the foundation of this proposal is to test the hypothesis that targeting biological aging pathways independently and in conjunction with disease-specific gene therapies may provide a promising avenue to develop new therapeutic strategies targeting neurodegeneration. My doctoral project investigates Kinesin-1 Family Member 5A (KIF5A), a known susceptibility gene for the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Mutant Kif5a mice demonstrate loss of functional MUs in the context of injury and aging, with observable pathological correlates. These data support a prominent role of KIF5A in MU maintenance, suggesting mutant KIF5A is unable to combat biological challenges such as injury or age. The F99 phase of this award will test the hypothesis that ALS-associated Kif5a mutations lead to haploinsufficiency and use viral vectors to manipulate Kif5a expression. The K00 phase will build upon my experience with MU physiology, pathology and viral vectors to study aging and neurodegeneration more broadly. As a postdoc, I will study the interdependence between physiological triggers of disease (genome and exposome), biological aging, and phenotype. Specifically, the proposed work will investigate AAV-mediated cellular reprogramming of transcription factors Oct4, Sox2, and Klf4 to improve MU longevity, resilience and repair, and then apply this approach to genetic MU disease. Aim 2A will test the effect of induced, transient reprogramming of individual MU cell types on functional, epigenetic, transcriptomic, and histopathological outcomes. Aim 2B will investigate the value of cellular reprogramming in enhancing aged MU repair and resilience when faced with MU insults. Aim 2C will test the utility of multi-transgene delivery of longevity-promoting cellular reprogramming independently and in conjunction with existing gene therapies to have a synergistic effect on disease phenotype. These studies will provide critical information about mechanisms of MU longevity, resilience and repair and will test a therape... ## Key facts - **NIH application ID:** 10840936 - **Project number:** 5K00AG079815-03 - **Recipient organization:** HARVARD MEDICAL SCHOOL - **Principal Investigator:** Kelly Rich - **Activity code:** K00 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $76,273 - **Award type:** 5 - **Project period:** 2022-12-01 → 2027-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10840936 ## Citation > US National Institutes of Health, RePORTER application 10840936, Cellular reprogramming to promote longevity, resilience, and repair in motor unit degeneration (5K00AG079815-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10840936. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*