The Role of Integrin Linked Kinase in Skeletal Muscle

描述（由申请人提供）：整合素在肌营养不良症的发病机制中起关键作用。整联蛋白可以补偿肌营养不良蛋白-肌营养不良蛋白聚糖复合物的缺陷，并且整联蛋白中的突变引起某些形式的肌营养不良。整合素执行这些功能的途径尚不清楚。整合素连接激酶（ILK）对无脊椎动物的肌肉功能非常重要，并被证明参与肌肉分化。其表达在心脏毒素引起的肌肉损伤后增加。我们想测试ILK对肌肉功能很重要的假设，特别是它在损伤后肌肉的恢复中起作用。我们将使用遗传方法来创建骨骼肌中ILK缺失的小鼠。将检查突变成肌细胞和肌肉组织的增殖、分化、粘附和存活缺陷。ILK作为细胞骨架适配器和肌肉中的激酶的作用将得到解决。两种小鼠损伤模型，心脏毒素注射和肌营养不良蛋白/ILK双突变体，将用于测试ILK在肌肉再生中的作用。这些研究将导致更好地了解肌肉中的整合素信号传导，并确定可能最终作为肌营养不良症治疗靶点的途径。

DESCRIPTION (provided by applicant): Integrins play key roles in the pathogenesis of muscular dystrophies. Integrins can compensate for defects of the dystrophin-dystroglycan complex, and mutations in integrins cause certain forms of muscular dystrophy. The pathways by which integrins carry out these functions are not understood. Integrin Linked Kinase (ILK) is important for muscle function in invertebrates and was shown to be involved in muscle differentiation. Its expression is increased following muscle injury with cardiotoxin. We would like to test the hypothesis that ILK is important for muscle function, and in particular, that it plays a role in recovery of muscle following injury. We will use a genetic approach to create mice with ILK deletion in skeletal muscle. Mutant myoblasts and muscle tissue will be examined for defects in proliferation, differentiation, adhesion and survival. The role of ILK as a cytoskeletal adaptor and as a kinase in muscle will be addressed. Two murine injury models, cardiotoxin injection and dystrophin/ILK double mutants, will be used to test the role of ILK in muscle regeneration. These studies will lead to a better understanding of integrin signaling in muscle and define the pathways that may eventually serve as targets for muscular dystrophy therapy.