Friday, July 26, 2024
7/26/2024
PROJECT SUMMARY Muscular dystrophies (MDs) are heritable neuromuscular diseases that cause progressive weakness and loss of muscle as regenerative processes fail to adequately respond to progressive muscle damage. This ultimately results in the replacement of functional musculature with a pathological extracellular matrix (ECM) composed of fibrosis and fat, known as a fibro-matrix, which is a prominent feature of the most common of the MDs, Duchenne MD (DMD). Effective therapeutics to combat fibro-matrix development and facilitate muscle regeneration are a major unmet clinical need for MD patients, however, the mechanisms responsible for these issues are not well understood. This project investigates cellular mechanisms contributing to the failed regeneration and fibrosis development in dystrophic muscle. Specifically, NAD(P)H oxidase 4 (NOX4) has been identified as an anti- fibrotic and pro-regenerative target in muscle. This was demonstrated by marked reductions in muscle fibrosis and beneficial muscle remodeling of severely dystrophic muscle that models DMD, where NOX4 was targeted using genetic and pharmacological approaches. It is hypothesized that NOX4 expression in myofibroblasts, cells that produce ECM following tissue injury, contributes to muscle fibrosis by preventing myofibroblast clearance following muscle regeneration. This phenomenon is known as myofibroblast persistence. The experiments of this project will rigorously investigate the mechanisms leading to and the pathological consequences resulting from the development of myofibroblast persistence using innovative genetic models, in vitro assays, and transcriptomic analyses. Aim 1 will investigate myofibroblast dynamics in dystrophic skeletal muscle using myofibroblast fate-mapping and conditional ablation of NOX4. Myofibroblast persistence will be assessed in a newly-developed assay using cells isolated from dystrophic muscle, and several in vitro assays will be employed to investigate myofibroblast behavior during differentiation and development of persistence. Aim 2 will evaluate the influence that myofibroblasts exert on gene expression and cellular behavior of myogenic, fibroblastic, and immune cells in dystrophic and regenerating muscle. In vitro models will be used to discern physical versus diffusible cues responsible for these myofibroblast-driven phenotypes. The ultimate goal of the current project is to define the pathological consequences of myofibroblasts in chronic muscle disease and provide solid mechanistic insight responsible for the efficacious impact of NOX4-targeting as a beneficial remodeling therapeutic strategy for the treatment of MDs and, potentially, other forms of muscle pathology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
