Regulating fibrosis and muscle growth in the muscular dystrophies

描述（由申请人提供）：肌肉萎缩症是一种无法治愈的遗传性疾病。肌营养不良最严重的形式之一是杜氏肌营养不良（DMD）。DMD和肢带肌营养不良症的一个子集有共同的肌营养不良蛋白复合物的破坏。破坏肌营养不良蛋白复合体会导致脆弱的肌膜，肌纤维的损失和肌肉纤维化或瘢痕的替代。多种证据表明纤维化是肌营养不良病理的驱动因素。我们假设纤维化提供了一个支架，促进不利的细胞因子谱，进一步损害肌肉。我们进一步假设，不利的细胞因子谱的主要成分是TGFp和相关的TGFp家族成员肌生成抑制素。TGFp和肌肉生长抑制素共同导致纤维化增加，肌肉质量和再生减少，并加剧了膜的脆弱性。因此，我们建议确定TGFp和肌肉生长抑制素通常被基质隔离的方式，使其无法参与受体接合和信号传导，并确定如何促进肌肉萎缩症中TGFp和肌肉生长抑制素的失活（项目1）。我们还将展示肌肉生长抑制素和相关分子释放和加工所需的蛋白水解裂解步骤，以及可溶性受体在治疗肌肉萎缩症中的有效程度（项目2）。我们还将依次评估由TGFp和肌生长抑制素触发的不同细胞内信号通路，并测试抑制这些通路是否能改善肌营养不良患者的肌肉功能和病理（项目3）。三位已成立的研究者（McNally， Lee和Molkentin）将领导这些项目，组成一个独特的团队，他们的综合专业知识将定义TGFp/肌生长抑制素途径，以治疗肌肉萎缩症。三个核心将支持这些项目；核心A将整合我们三个机构的努力，以确保材料的无缝协作和转移。Core B将提供基因操作和治疗后肌肉萎缩症的组织病理学评估，Core C将进行体内功能分析并为Core B提供支持。

DESCRIPTION (provided by applicant): Muscular dystrophy is a genetic disease for which there is no cure. One of the most severe forms of muscular dystrophy is Duchenne Muscular Dystrophy (DMD). DMD and a subset of the limb girdle muscular dystrophies have in common disruption of the dystrophin protein complex. Disrupting the dystrophin complex lead to a fragile muscle membrane, loss of myofibers and replacement of the muscle with fibrosis or scarring. Multiple lines of evidence point to fibrosis is as a driver of muscular dystrophy pathology. We hypothesize that fibrosis provides a scaffold that promotes an unfavorable cytokine profile that further damages muscle. We further hypothesize that the primary components of the unfavorable cytokine profile are TGFp and the related TGFp family member myostatin. Together, TGFp and myostatin, lead to increased fibrosis, reduced muscle mass and regeneration, and aggravated membrane fragility. Therefore, we propose to determine the means by which TGFp and myostatin are normally sequestered by the matrix and held unavailable for receptor engagement and signaling and to determine how to promote inactivation of TGFp and myostatin in muscular dystrophy (Project 1). We will also demonstrate necessary proteolytic cleavage steps for release and processing of myostatin, and related molecules, and the degree to which soluble receptors can be effective in treating muscular dystrophy (Project 2). We will also sequentially assess the distinct intracellular signaling pathways that are triggered by TGFp and myostatin and test whether inhibiting these pathways improves muscle function and pathology in muscular dystrophy (Project 3). Three established investigators (McNally, Lee, and Molkentin) will lead these projects forming a distinctive team where their combined expertise will define the TGFp/myostatin pathway for therapeutic intent in muscular dystrophy. Three Cores will support the Projects; Core A will integrate the efforts at our three institutions to assure seamless collaboration and transfer of materials. Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B.