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Understanding the Mechanisms of Fibrosis in Muscular Dystrophies

了解肌营养不良症纤维化的机制

基本信息

批准号：
10718804
负责人：
DAVID W HAMMERS
金额：
$ 49.53万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-12 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718804
关键词：
Ablation Affect Behavior Biological Assay Biological Models Cell Separation Cell secretion Cells Chronic Clinical Collaborations Cues Data Deposition Development Disease Disease Progression Duchenne muscular dystrophy Exhibits Extracellular Matrix Fatty acid glycerol esters Fibrosis Foundations Future Gene Expression Genetic Genetic Models Goals Heritability Imaging Techniques Immune Immunologics Impairment In Vitro Inflammation Investigation Label Maps Methodology Modeling Muscle Muscle Development Muscular Atrophy Muscular Dystrophies Myofibroblast Myopathy Natural regeneration Neuromuscular Diseases Oxidases Pathologic Pathology Patients Pattern Phenotype Population Prevalence Process Publishing Regenerative capacity Regulation Rejuvenation Research Role Skeletal Muscle Solid Source Testing Therapeutic Tissues Work cell behavior cell motility cell type combat efficacious treatment experimental study improved in vitro Assay in vitro Model in vivo innovation insight mouse model muscle form muscle regeneration pharmacologic prevent regenerative satellite cell therapeutically effective tissue injury transcriptomics translational approach translational potential treatment strategy

项目摘要

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.

项目总结