Calcium Regulation in the Progression of Muscular Dystrophy

肌营养不良症进展中的钙调节

• 批准号: 8230611
• 负责人: Noah Weisleder
• 金额: $ 24.9万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-18 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230611
• 关键词: Actins; Address; Affect; Animal Model; Animals; Ants; Biological Assay; Breeding; Calcium; Cells; Characteristics; Code; Complex; Confocal Microscopy; Coupling; Cytoskeleton; Data; Defect; Development; Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Epithelial Cells; Event; Extracellular Matrix; Extracellular Space; Fiber; Foundations; Generations; Genes; Goals; Hereditary Disease; Homeostasis; Image; In Vitro; Instruction; Knowledge; Laminin; Link; Measurement; Mediating; Mediator of activation protein; Membrane; Mentors; Methods; Microscopic; Molecular; Muscle; Muscle Cells; Muscle Fibers; Muscular Dystrophies; Mutation; Myopathy; PLA2G6 gene; Pathology; Pathway interactions; Patients; Phase; Phenotype; Phospholipase; Phospholipase A2; Preparation; Regulation; Research; Role; Severities; Signal Transduction; Skeletal Muscle; Smooth Muscle Myocytes; Stress; Striated Muscles; Structure; Testing; Training; United States; base; extracellular; insight; link protein; mdx mouse; mouse model; muscle degeneration; patch clamp; reagent testing; research study; response

Duclienne muscular dystrophy is a common genetic disorder resulting from mutations within the dystrophin gene. It is likely that the dystrophic phenotype does not result directly from alteration to the myofibrillar Structures, rather it is a disruption of sarcolemmal membrane integrity that nomnally confers tight control of intracellular Ca homeostasis, which leads to elevated intracellular Ca and eventual muscle degeneration. The pathophysiological mechanism responsible for elevation of intracellular Ca levels is not dear, however our recent findings suggest that store-operated Ca entry (SOCE) linked to uncontrolled Ca spark activity may contribute to the aberrant Ca influx observed in dystrophic muscle. While the mechanism of SOCE activation is still a matter of intensive study, it has been recently detemnined that the Ca insensitive phospholipase A2 (iPLA2) is an important mediator of SOCE. The focus of this project is to test the hypothesis that aben-ant Ca spark activity acts as a trigger for SOCE and thus induces a dystrophic cascade in mammalian skeletal muscle through a pathway that involves iPLA2 mediated signaling. We will test this with three specific aims: Aim 1; To establish induced Ca sparks as a trigger for SOCE in healthy and dystrophic muscle. We will utilize multiple methods for measurement of SOCE to examine alteration to Ca entry in dystrophic fiber. Patch-clamp measurement and modulation of Oa influx will provide insight into SR Ca release and the activation of SOCE in dystrophic fibers. Aim 2: Detemiine the contribution of iPLA2 activity to Ca influx in muscular dystrophy. We will examine the altered characteristics of iPLA2 function in dystrophic muscle using various in vitro molecular and pharmacological methods. Aim 3: To elucidate if SOCE facilitates the dystrophic cascade in skeletal muscle. Due to the inability to assess changes in the dystrophic phenotype in skeletal muscle we wili modulate SOCE in dystrophic animals and assay changes in dystrophic phenotypes.

杜氏肌营养不良症是一种常见的由肌营养不良蛋白突变引起的遗传性疾病