# Cellular reprogramming to promote longevity, resilience, and repair in motor unit degeneration

> **NIH NIH K00** · HARVARD MEDICAL SCHOOL · 2024 · $75,600

## 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).
Genetic variants may accelerate biological aging and acquired cellular damage in the nervous
system. Aged mammalian tissues retain an epigenetic signature, and recent publications highlight
multiple strategies to restore youthful tissue resilience, such as cellular reprogramming. My long-
term career goal is to obtain a tenure-track clinician-scientist position at an academic institution
and establish a translational research program. My long-term scientific goal is 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 for treatment development. The K00 phase will build upon my
experience during the F99 phase by leveraging 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 test a therapeutic approach which has implications for all age-related neurodegenerative
disease. Beyond this, the proposed career development plan has been thoughtfully designed to
develop the technical expertise, science communication skills, and mentorship experience
essential to becoming an independent investigator.

## Key facts

- **NIH application ID:** 11081266
- **Project number:** 3K00AG079815-03S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Kelly Rich
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,600
- **Award type:** 3
- **Project period:** 2022-12-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11081266

## Citation

> US National Institutes of Health, RePORTER application 11081266, Cellular reprogramming to promote longevity, resilience, and repair in motor unit degeneration (3K00AG079815-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11081266. Licensed CC0.

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