Ciliary Hedgehog signaling during adult tissue repair and disease

成人组织修复和疾病期间的睫状刺猬信号传导

基本信息

批准号：
10444402
负责人：
Daniel Kopinke
金额：
$ 33.41万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444402
关键词：
Acute Address Adipocytes Adult Affect Ants Biological Assay Biology Cells Chronic Cicatrix Cilia Coculture Techniques Data Development Diabetes Mellitus Direct Lytic Factors Disease Duchenne muscular dystrophy Endothelial Cells Equilibrium Erinaceidae Fatty acid glycerol esters Fibrosis Genetic Glycerol Goals Health Histology In Vitro Infiltration Injury Intramuscular Knowledge Ligands Measurement Modeling Molecular Muscle Muscle function Muscle satellite cell Muscular Atrophy Myopathy Natural regeneration Neuromuscular Diseases Obesity Outcome Pathogenicity Pathway interactions Pharmacology Positioning Attribute Publishing Regenerative capacity Reporting Role SHH gene Schwann Cells Signal Pathway Signal Transduction Sonication System Testing Time Tissues Work age related cell type combat experimental study human disease improved in vivo innovation insight intercellular communication interstitial knockout animal lipid biosynthesis mdx mouse mouse model muscle form muscle regeneration muscle strength myogenesis novel novel therapeutic intervention preservation prevent progenitor regeneration function repaired sarcopenia skeletal muscle wasting smoothened signaling pathway therapeutic development tissue repair tool

项目摘要

Project Summary Fatty fibrosis, the replacement of healthy muscle tissue with fat and fibrotic scar tissue, is a prominent feature of chronic muscle diseases such as Duchenne muscular dystrophy (DMD), sarcopenia, the age-related loss of skeletal muscle and strength, in addition to obesity, and diabetes. This project will identify and characterize the cellular and molecular mechanisms by which intramuscular fat forms, and the functional consequences of intramuscular fat on muscle health. Recent evidence points to ciliary Hedgehog signaling as a potent ant- adipogenic signal during muscle regeneration and in mdx mice, a mouse model of DMD. In addition, Hedgehog promotes muscle repair and prevents the decline in myofiber size in mdx mice. By what mechanism(s) Hedgehog acts to balance fat formation and muscle regeneration is unknown. This proposal will use innovative and powerful mouse models to identify the role of Hedgehog signaling during muscle regeneration in the following aims: 1) Identify and characterize the responsible Hedgehog ligand; 2) determine which cell types respond to Hedgehog signaling; and 3) demonstrate if intramuscular fat directly affects muscle health. Taken together, this proposal will provide insights into the origin and function of intramuscular fat and will aid in the search for novel therapeutic interventions into human diseases affected by fatty fibrosis.

项目概要脂肪纤维化，即健康肌肉组织被脂肪和纤维化疤痕组织替代，是脂肪纤维化的一个显着特征。慢性肌肉疾病，如杜氏肌营养不良症 (DMD)、肌肉减少症、与年龄相关的肌肉减少症骨骼肌和力量，除了肥胖和糖尿病。该项目将确定并描述肌内脂肪形成的细胞和分子机制，以及其功能后果肌内脂肪对肌肉健康的影响。最近的证据表明睫状刺猬信号是一种有效的蚂蚁肌肉再生期间和 mdx 小鼠（DMD 小鼠模型）中的脂肪生成信号。此外，刺猬促进 mdx 小鼠的肌肉修复并防止肌纤维尺寸下降。通过什么机制刺猬平衡脂肪形成和肌肉再生的作用尚不清楚。该提案将使用创新且强大的小鼠模型以确定 Hedgehog 信号在肌肉再生过程中的作用，目标如下：1) 识别并表征负责的 Hedgehog 配体； 2) 确定哪些细胞类型对 Hedgehog 有反应信号发送； 3）证明肌内脂肪是否直接影响肌肉健康。综合起来，这个提案将深入了解肌内脂肪的起源和功能，并有助于寻找新的治疗方法对受脂肪纤维化影响的人类疾病进行干预。