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