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Regulation of muscle fiber type and resistance to muscular dystrophy

调节肌纤维类型和抵抗肌营养不良症

基本信息

批准号：
8998925
负责人：
Lisa Maves
金额：
$ 9.75万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8998925
关键词：
Address Affect Animal Model Calcium Cellular Metabolic Process Chemicals Clinical Development Disease Duchenne muscular dystrophy Dystrophin Embryo Epigenetic Process FDA approved Fiber Genes Genetic Genetic Programming Genetic screening method Goals Health Hereditary Disease Human Knowledge Lesion Libraries Life Mammals Membrane Modeling Modification Muscle Muscle Development Muscle Fibers Muscle function Muscular Atrophy Muscular Dystrophies Myosin Heavy Chains Outcome Pathway interactions Pharmaceutical Preparations Phenotype Predisposition Process Property Public Health Regulation Reporter Research Resistance SHH gene Skeletal Muscle Testing Therapeutic Therapeutic Effect Therapeutic Studies Transcriptional Regulation Transgenic Organisms Work Zebrafish base chemical genetics epigenetic drug homeodomain improved innovation mouse model muscle degeneration programs screening skeletal muscle differentiation small molecule libraries success symptomatic improvement transcription factor

项目摘要

DESCRIPTION (provided by applicant): Certain muscular dystrophies preferentially affect a specific skeletal muscle fiber type, either fast or slow twitch. In particular, fast muscle fibers re more susceptible to damage than slow fibers in human and mouse models of Duchenne Muscular Dystrophy (DMD). In the mouse model, many genetic and epigenetic factors can ameliorate the effects of DMD, possibly by promoting a slow muscle phenotype. However, it is not clear from these studies whether fiber type identity is indeed essential for conferring susceptibility or resistance to muscular dystrophy. This project is aimed at an ultimate goal of manipulating skeletal muscle fiber type as a treatment for muscular dystrophy. The objectives of this proposal are to systematically test whether genetic and epigenetic regulators of fiber-type identity can modulate the muscular dystrophy phenotype and to identify new epigenetic molecules that regulate fiber-type differentiation. This proposal will directly test a fundamental hypothesis: that factors that promote slow muscle differentiation will ameliorate the effects of DMD. Recent studies, including work from our lab, have identified critical genetic and epigenetic mechanisms that regulate fiber-type identity. These studies now create an opportunity to directly test whether fiber-type modulation is a viable therapeutic approach for muscular dystrophies and to identify candidate molecules that will provide the basis for therapeutic studies in zebrafish and, ultimately, in mammals. This proposal will take advantage of zebrafish models to address two Specific Aims. Aim 1 will directly test whether muscle fiber type confers susceptibility or resistance to muscular dystrophy by determining whether factors that regulate fiber-type differentiation enhance or suppress the zebrafish dmd phenotype. We will initiate our approach by manipulating fiber-type regulators that function early in development in zebrafish embryos lacking Dystrophin. Aim 2 will identify new epigenetic factors that regulate muscle fiber type by screening an epigenetic chemical library using live trans- genic zebrafish that co-express fluorescent reporters for fast and slow muscle. The epigenetic chemicals will also be screened for their abilities to enhance or suppress the zebrafish dmd phenotype. This project will thus identify genetic and epigenetic regulators of muscle fiber-type identities that confer susceptibility or resistance to muscular dystrophy. These expected outcomes are significant because the genetic and epigenetic regulators identified by this proposal are highly likely to provide new targets for therapeutic studies. The recent success of epigenetic chemical screening in other developmental and disease processes highlights the exceptional opportunity and innovation such screening will provide for the skeletal muscle differentiation and muscular dystrophy fields.

描述（由申请人提供）：某些肌营养不良症优先影响特定的骨骼肌纤维类型，无论是快速或缓慢抽搐。特别是，在杜氏肌营养不良（DMD）的人类和小鼠模型中，快肌纤维比慢肌纤维更容易受到损伤。在小鼠模型中，许多遗传和表观遗传因素可以改善DMD的影响，可能是通过促进慢肌表型。然而，从这些研究中还不清楚纤维类型的同一性是否确实是赋予肌营养不良症的易感性或抵抗力所必需的。该项目旨在最终目标是操纵骨骼肌纤维类型作为肌营养不良症的治疗。本提案的目的是系统地测试纤维类型身份的遗传和表观遗传调节剂是否可以调节肌营养不良症表型，并确定新的表观遗传分子，调节纤维类型分化。该提案将直接测试一个基本假设：促进缓慢肌肉分化的因素将改善DMD的影响。最近的研究，包括我们实验室的工作，已经确定了调节纤维类型身份的关键遗传和表观遗传机制。这些研究现在创造了一个机会，可以直接测试纤维类型调制是否是肌营养不良症的可行治疗方法，并确定候选分子，这些分子将为斑马鱼和最终哺乳动物的治疗研究提供基础。该提案将利用斑马鱼模型来解决两个特定目标。目的1将通过确定调节肌纤维类型分化的因子是增强还是抑制斑马鱼dmd表型，直接测试肌纤维类型是否赋予对肌营养不良症的易感性或抵抗力。我们将通过操纵在缺乏Dystrophin的斑马鱼胚胎发育早期起作用的纤维型调节剂来启动我们的方法。目标2将通过使用共表达快肌和慢肌荧光报告基因的活转基因斑马鱼筛选表观遗传化学库来识别调节肌纤维类型的新表观遗传因子。表观遗传化学物质也将被筛选，以确定它们增强或抑制斑马鱼dmd表型的能力。因此，该项目将确定赋予肌营养不良症易感性或抵抗力的肌纤维类型身份的遗传和表观遗传调节因子。这些预期的结果是重要的，因为该提案所确定的遗传和表观遗传调节因子极有可能为治疗研究提供新的靶点。最近表观遗传化学筛选在其他发育和疾病过程中的成功凸显了此类筛选将为骨骼肌分化和肌肉萎缩症领域提供的绝佳机会和创新。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity.

BMP 和 FGF 信号传导通过控制基本螺旋-环-螺旋转录因子活性与模式中胚层相互作用。

DOI：
10.7554/elife.31018
发表时间：
2018
期刊：
eLife
影响因子：
7.7
作者：
Row,RichardH;Pegg,Amy;Kinney,BrianA;Farr3rd,GistH;Maves,Lisa;Lowell,Sally;Wilson,Valerie;Martin,BenjaminL
通讯作者：
Martin,BenjaminL

A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy.

DOI：
10.1186/s13395-020-00251-4
发表时间：
2020-10-15
期刊：
Skeletal muscle
影响因子：
4.9
作者：
Farr GH 3rd;Morris M;Gomez A;Pham T;Kilroy E;Parker EU;Said S;Henry C;Maves L
通讯作者：
Maves L

Recent advances using zebrafish animal models for muscle disease drug discovery.