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发挥关键作用。整合素可以弥补营养不良蛋白-营养不良多糖复合体的缺陷，整合素的突变会导致某些形式的肌肉营养不良。整合素执行这些功能的途径尚不清楚。整合素连接蛋白激酶(ILK)对无脊椎动物的肌肉功能起重要作用，并被证明参与肌肉分化。心脏毒素致肌肉损伤后，其表达增加。我们想要验证的假设是，ILK对肌肉功能很重要，尤其是在损伤后的肌肉恢复中发挥作用。我们将使用遗传方法来创造骨骼肌ilk缺失的小鼠。突变的成肌细胞和肌肉组织将接受增殖、分化、黏附和存活方面的缺陷检查。ILK在肌肉中作为细胞骨架适配器和作为一种激酶的作用将被讨论。两种小鼠损伤模型，心脏毒素注射和dystrophin/ilk双突变，将被用来测试ilk在肌肉再生中的作用。这些研究将有助于更好地了解肌肉中的整合素信号，并确定最终可能成为肌肉营养不良治疗靶点的途径。

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.