The Role of Cytokeratins in Skeletal Muscle Injury

这项研究的目的是增加对肌肉损伤、治疗和恢复的潜在机制的了解。我的假设是，细胞角蛋白K8和K19在骨骼肌肌膜的组织和功能中起着不可或缺的作用。我将使用功能、形态和分子生物学方法通过三个具体目标来验证这一假说：1)a)使小鼠肌肉损伤的模型适用于小鼠，并将随后的收缩功能与已知的营养不良症小鼠(mdx小鼠)进行比较；b：比较mdx和野生型(Wt)单纤维的力量与整个肌肉的发现以及与mdx纤维相比，2)确定缺乏细胞角蛋白k8或k19的肌肉是否营养不良和/或更容易受到损伤，以及是否通过腺病毒转染腺病毒将缺失的亚单位替换为肌肉纤维来纠正营养不良或改变对损伤的易感性。3)了解K8或K19的过度表达是否会导致肌病。某些肌营养不良的组织病理学与损伤引起的肌肉变化有明显的相似性。这项拟议的研究旨在阐明一些共同的细胞和分子机制。

The goal of this research is to increase understanding of the mechanisms underlying muscle injury, treatment, and recovery. My hypothesis is that cytokeretins K8 & K19 play an integral part in the organization and function of the sarcolemma of skeletal muscle. I will use functional, morphological, and molecular biological approaches to test this hypothesis through 3 specific aims: 1) a: To adapt a model of muscle injury to mice and compare subsequent contractile function to mice with a known dystrophinopathy (mdx mice), b: to compare forces of mdx and wild-type (wt) single-fibers to the whole-muscle findings and to mdx fibers transfected with a virus expressing a functional dystrophin, 2) To determine whether muscles lacking cytokeratin K8 or K19 are dystrophic and/or more susceptible to injury, and if replacement of the missing subunit into muscle fibers by adenoviral transfection corrects the dystrophy or alters susceptibility to injury, 3) To learn if overexpression of K8 or K19 results in myopathy. There are marked similarities in the histopathology of some muscular dystrophies and the changes in muscle induced by injury. The proposed research is designed to elucidate some of the shared cellular and molecular mechanisms.