Regulating fibrosis and muscle growth in the muscular dystrophies

描述(申请人提供)：肌营养不良症是一种无法治愈的遗传性疾病。Duchenne肌营养不良症(DMD)是最严重的肌营养不良症之一。DMD和肢带型肌营养不良症的一部分共同破坏了肌营养不良蛋白复合体。破坏肌营养不良蛋白复合体会导致脆弱的肌膜，失去肌纤维，并以纤维化或疤痕取代肌肉。多条线的证据表明，纤维化是肌肉营养不良病理的驱动因素。我们假设，纤维化提供了一种支架，促进了不利的细胞因子谱，进一步损害了肌肉。我们进一步假设，不利的细胞因子谱的主要成分是TGFp及其相关的TGFp家族成员myostatin。TGFp和myostatin共同导致纤维化增加，肌肉质量和再生减少，并加重膜的脆性。因此，我们建议确定TGFp和myostatin通常被基质隔离而不能用于受体参与和信号传递的方式，并确定如何在肌营养不良症中促进TGFp和myostatin的失活(项目1)。我们还将演示释放和处理肌肉生长抑素及其相关分子所需的蛋白分解步骤，以及可溶性受体在治疗肌营养不良症中的有效程度(项目2)。我们还将依次评估由TGFp和myostatin触发的不同的细胞内信号通路，并测试抑制这些通路是否改善了肌营养不良症的肌肉功能和病理(项目3)。三位资深研究人员(McNally、Lee和Molkentin)将领导这些项目，组成一个独特的团队，他们的专业知识将共同定义肌营养不良症治疗意图的TGFp/myostatin途径。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，以确保无缝协作和材料转让。核心B将对基因操作和治疗后的肌营养不良症进行组织病理学评估，核心C将在体内进行功能分析，并为核心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.