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T-tubule membrane remodeling in Drosophila myofiber function and models of myopathy

果蝇肌纤维功能和肌病模型中的 T 管膜重塑

基本信息

批准号：
10633659
负责人：
AMY A KIGER
金额：
$ 11.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10633659
关键词：
Address Adult Age Aging Animals Atrophic Autophagocytosis Biological Assay Cardiovascular Diseases Cell membrane Cell physiology Cell surface Cells Cellular Structures Centronuclear myopathy Development Disease Disease model Drosophila genus Dynamin Endocytosis Genes Genetic Genetic Screening Guanosine Triphosphate Phosphohydrolases Health Heart failure Human Life Lighting Maintenance Mediating Membrane Modeling Molecular Molecular Genetics Muscle Muscle Cells Muscle Contraction Muscle function Myocardial Ischemia Myopathy Pathway interactions Physiological Protein Biochemistry Proteins Publishing Regulation Research Role Sarcomeres Sarcoplasmic Reticulum Shapes Signal Transduction Stress Structure System Therapeutic Intervention Translating Tubular formation Work cellular imaging fly gene function human disease improved in vivo in vivo imaging innovation mutant novel novel therapeutic intervention programs response skeletal tool trafficking

项目摘要

Project Summary Muscles are highly specialized and organized cells that provide contraction essential for animal life. A disruption of the elaborate, functional muscle cell organization underlies human myopathy diseases. In particular, differentiation of the muscle cell membrane into an extensive tubular membrane network called Transverse (T)-tubules is needed to enable signaling that coordinates power of muscle contraction. T-tubule disorganization or loss is observed in certain human skeletal myopathies and cardiovascular diseases, and interestingly, associated mutant genes encode for membrane regulators with known wildtype roles outside of muscle in endocytosis or endosomal trafficking. While there are speculations on mechanisms, it remains to be determined how implicated endocytic functions may contribute to T-tubule maintenance. Relatively little is known about the molecular-genetic basis for how T-tubules form nor the dynamics or remodeling mechanisms in intact muscle in response to muscle cell use, damage or aging. In flies, we uncovered regulated T-tubule remodeling and the identity of specific conserved gene functions involved at distinct disassembly-reassembly stages during a wildtype developmental myofiber remodeling program. Importantly, specific T-tubule remodeling roles for fly homologs of two human genes disrupted in centronuclear myopathy point to the significance of T-tubule dynamics and the ability to study in models of disease. The fly system affords the unique and key advantages of live, in vivo imaging of T-tubule dynamics in intact myofibers within a stereotypical developmental timeframe in combination with a wealth of genetic tools. Following results from genetic screens, we established a new framework understanding of T-tubule dynamics that includes a central role for dynamin large GTPase activity in T-tubule disassembly and subsequent membrane progression into specific endosomal and autophagy trafficking needed for remodeling. Using our innovative genetic, cellular and molecular approaches in intact fly muscles, here we will build on our novel findings to determine the mechanisms and regulation of dynamin-mediated T-tubule disassembly by vesiculation, and establish the identity of a proposed novel Rab35 endosomal pathway and the relationship to autophagy both needed for progression from disassembly to remodeling. Importantly, we will translate our understanding of a developmental program for T-tubule remodeling to adult flight muscle. We will establish conservation and consequences of a pathway activity for T-tubule membrane reorganization in ongoing adult muscle function, with relevance to understanding human muscle disease.

项目总结