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Regulating fibrosis and muscle growth in the muscular dystrophies

调节肌营养不良症中的纤维化和肌肉生长

基本信息

批准号：
8868179
负责人：
Elizabeth M McNally
金额：
$ 122.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868179
关键词：
Adult Affect Binding Binding Proteins Cells Child Cicatrix Cleaved cell Collaborations Collagen Complex Data Deposition Disease Doctor of Medicine Doctor of Philosophy Duchenne muscular dystrophy Dyes Dystrophin Evans blue stain Family member Fibrosis Genes Genetic Genetic screening method Goals Growth Hereditary Disease Infiltration Institution Knockout Mice Laboratories Lead Length Limb-Girdle Muscular Dystrophies Measures Mediating Membrane Modeling Molecular Genetics Muscle Muscle Weakness Muscle function Muscular Dystrophies Natural regeneration Outcome Outcome Measure Pathogenesis Pathology Pathway interactions Peptide Hydrolases Play Principal Investigator Process Research Research Personnel Role Sarcoglycans Signal Pathway Signal Transduction TGFB1 gene Techniques Testing Therapeutic base cytokine genetic manipulation improved in vivo mouse model muscle degeneration muscle form muscle regeneration myostatin overexpression protein complex public health relevance receptor research study scaffold uptake

项目摘要

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.

描述（由申请人提供）：肌营养不良症是一种无法治愈的遗传性疾病。最严重的肌营养不良症之一是杜氏肌营养不良症 (DMD)。 DMD 和肢带型肌营养不良症的一个共同点是肌营养不良蛋白复合物遭到破坏。破坏肌营养不良蛋白复合物会导致肌膜脆弱、肌纤维丧失以及肌肉纤维化或疤痕替代。多种证据表明纤维化是肌营养不良病理学的驱动因素。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细胞因子谱的主要成分是 TGFp 和相关的 TGFp 家族成员肌肉生长抑制素。 TGFβ 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以及膜脆性加剧。因此，我们建议确定 TGFβ 和肌生长抑制素通常被基质隔离并且无法与受体结合和信号传导的方式，并确定如何促进肌营养不良症中 TGFβ 和肌生长抑制素的失活（项目 1）。我们还将展示释放和加工肌生长抑制素及相关分子所必需的蛋白水解裂解步骤，以及可溶性受体在治疗肌营养不良症方面的有效程度（项目 2）。我们还将依次评估由 TGFβ 和肌生成抑制素触发的不同细胞内信号传导途径，并测试抑制这些途径是否可以改善肌营养不良症的肌肉功能和病理学（项目 3）。三名知名研究人员（McNally、Lee 和 Molkentin）将领导这些项目，组建一个独特的团队，他们的综合专业知识将定义 TGFp/肌生长抑制素途径，以实现肌营养不良症的治疗目的。三个核心将支持这些项目； Core A 将整合我们三个机构的努力，以确保无缝协作和材料转移。 Core B将在基因操作和治疗后提供肌营养不良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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice.

Serpina3n 的基因过度表达可减轻小鼠的肌营养不良症。

DOI：
10.1093/hmg/ddw005
发表时间：
2016
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Tjondrokoesoemo,Andoria;Schips,Tobias;Kanisicak,Onur;Sargent,MichelleA;Molkentin,JefferyD
通讯作者：
Molkentin,JefferyD

Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.