The Role of Germline Mutations of the Ras/MAPK Pathway on Skeletal Myogenesis

Ras/MAPK 途径种系突变对骨骼肌生成的作用

基本信息

  • 批准号:
    8797011
  • 负责人:
  • 金额:
    $ 31.47万
  • 依托单位:
  • 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:
    2014-01-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Skeletal myogenesis is a dynamic process in which muscle precursor cells first proliferate and then fuse to form multinucleated myotubes that ultimately mature into skeletal muscle fibers. The Ras/Mitogen-activated protein kinase (MAPK) pathway, a well-studied cancer pathway, plays a critical role in the regulation of myogenesis, particularly during the switch from myoblast proliferation to differentiation. Early studies have demonstrated that high levels of Ras/MAPK pathway activation disrupt early myogenesis. However, there are critical gaps in our understanding as to how Ras and its downstream effector cascades regulate and affect vital steps in myogenesis during development. The "RASopathies", a newly defined group of medical genetic syndromes, are one of the largest groups of multiple congenital anomaly syndromes known, affecting more than 1 in 1000 individuals. Caused by germline mutations in various key genes encoding components of the Ras/MAPK pathway, the RASopathies share a common phenotypic feature of congenital hypotonia, or weak muscles. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two RASopathies with the most severe muscle phenotype. We have recently identified the presence of a novel myopathy, defined as an intrinsic abnormality of muscle that is not attributable to nerve dysfunction, in individuals with CS and CFC. In addition, our preliminary studies provide support for our hypothesis that dysregulation of Ras/MAPK signaling disrupts both early myogenesis by inhibiting myoblast differentiation, and later stages of muscle development following differentiation, by inhibiting muscle growth. The goal of the proposed research is to understand how myogenesis is affected by Ras/MAPK dysregulation, as well as the specific mechanism of action underlying this effect. We will examine novel germline mutations identified in the RASopathies to help us understand how Ras dysregulation affects muscle development. Our Specific Aims are designed to determine 1) how skeletal muscle is disrupted by dysregulation of Ras/MAPK pathway signaling in CS and CFC; 2) the mechanisms by which Ras/MAPK dysregulation causes disruption of skeletal muscle myogenesis, and 3) if small molecule inhibitors and small interfering RNAs (siRNA) can reverse the effects of dysregulated Ras/MAPK signaling during myogenesis. We will use mouse models of CS and CFC to elucidate how skeletal muscle is disrupted by distinguishing what aspect of the myopathy is due to inhibition of myoblast differentiation and what is due to muscle fiber formation from post-differentiation inhibition of muscle growth. We will elucidate the specific mechanisms by which Ras/MAPK signal dysregulation inhibits myogenesis using primary myoblasts derived from CS and CFC mouse models. Results derived from those experiments will be used to evaluate the effectiveness of rationally chosen inhibitors to correct the developmental effects of a dysregulated Ras pathway using in vitro and in vivo models of myogenesis.
描述(由申请人提供):骨骼肌发生是一个动态过程,其中肌肉前体细胞首先增殖,然后融合形成多核肌管,最终成熟为骨骼肌纤维。 Ras/丝裂原激活蛋白激酶 (MAPK) 途径是一种经过充分研究的癌症途径,在肌生成的调节中发挥着关键作用,特别是在从成肌细胞增殖到分化的转变过程中。早期研究表明,高水平的 Ras/MAPK 通路激活会破坏早期的肌生成。然而,我们对 Ras 及其下游效应级联如何调节和影响发育过程中肌生成的重要步骤的理解存在重大差距。 “RASopathies”是一组新定义的医学遗传综合征,是已知最大的多种先天性异常综合征之一,影响千分之一以上的个体。 RASo 病是由编码 Ras/MAPK 通路成分的各种关键基因的种系突变引起的,具有先天性肌张力低下或肌肉无力的共同表型特征。 Costello 综合征 (CS) 和心面皮肤 (CFC) 综合征是两种肌肉表型最严重的 RASo 病。我们最近在 CS 和 CFC 患者中发现了一种新型肌病的存在,这种肌病被定义为一种与神经功能障碍无关的内在肌肉异常。此外,我们初步 研究为我们的假设提供了支持,即 Ras/MAPK 信号传导失调会通过抑制成肌细胞分化来破坏早期肌生成,并通过抑制肌肉生长来破坏分化后的肌肉发育后期。本研究的目的是了解 Ras/MAPK 失调如何影响肌生成,以及这种效应的具体作用机制。我们将检查 RASopathies 中发现的新种系突变,以帮助我们了解 Ras 失调如何影响肌肉发育。我们的具体目标旨在确定 1) CS 和 CFC 中 Ras/MAPK 通路信号传导失调如何破坏骨骼肌; 2) Ras/MAPK 失调导致骨骼肌肌生成中断的机制,以及 3) 小分子抑制剂和小干扰 RNA (siRNA) 是否可以逆转肌生成过程中 Ras/MAPK 信号失调的影响。我们将使用 CS 和 CFC 小鼠模型,通过区分肌病的哪些方面是由于成肌细胞分化抑制所致,以及哪些方面是由于分化后抑制肌肉生长而导致肌纤维形成所致,从而阐明骨骼肌是如何受到破坏的。我们将使用来自 CS 和 CFC 小鼠模型的原代成肌细胞来阐明 Ras/MAPK 信号失调抑制肌生成的具体机制。这些实验的结果将用于评估合理选择的抑制剂的有效性,以使用体外和体内的肌生成模型来纠正失调的 Ras 途径的发育影响。

项目成果

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Katherine Anna Rauen其他文献

Katherine Anna Rauen的其他文献

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{{ truncateString('Katherine Anna Rauen', 18)}}的其他基金

The Role of Germline Mutations of the Ras/MAPK Pathway on Skeletal Myogenesis
Ras/MAPK 途径种系突变对骨骼肌生成的作用
  • 批准号:
    8904608
  • 财政年份:
    2014
  • 资助金额:
    $ 31.47万
  • 项目类别:
The Role of Germline Mutations of the Ras/MAPK Pathway on Skeletal Myogenesis
Ras/MAPK 途径种系突变对骨骼肌生成的作用
  • 批准号:
    8716527
  • 财政年份:
    2014
  • 资助金额:
    $ 31.47万
  • 项目类别:
The Role of Germline Mutations in the Ras/MAPK Pathway on Skeletal Myogenesis
Ras/MAPK 通路种系突变对骨骼肌生成的作用
  • 批准号:
    8519308
  • 财政年份:
    2012
  • 资助金额:
    $ 31.47万
  • 项目类别:
The Role of Germline Mutations in the Ras/MAPK Pathway on Skeletal Myogenesis
Ras/MAPK 通路种系突变对骨骼肌生成的作用
  • 批准号:
    8373408
  • 财政年份:
    2012
  • 资助金额:
    $ 31.47万
  • 项目类别:
Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back
Ras/MAPK 通路的遗传综合征:从床边到工作台再回来
  • 批准号:
    7674309
  • 财政年份:
    2009
  • 资助金额:
    $ 31.47万
  • 项目类别:
1st Costello Syndrome Symposium
第一届科斯特洛综合症研讨会
  • 批准号:
    7278088
  • 财政年份:
    2007
  • 资助金额:
    $ 31.47万
  • 项目类别:
Elucidation of the genetic etiology of Costello Syndrome
阐明科斯特洛综合征的遗传病因
  • 批准号:
    6851354
  • 财政年份:
    2005
  • 资助金额:
    $ 31.47万
  • 项目类别:
CLINICAL INVESTIGATION OF THE PATIENT WITH CHROMOSOME ABERRATIONS
染色体畸变患者的临床研究
  • 批准号:
    7204855
  • 财政年份:
    2005
  • 资助金额:
    $ 31.47万
  • 项目类别:
Elucidation of the genetic etiology of Costello Syndrome
阐明科斯特洛综合征的遗传病因
  • 批准号:
    7007345
  • 财政年份:
    2005
  • 资助金额:
    $ 31.47万
  • 项目类别:
Elucidation of the genetic etiology of Costello Syndrome
阐明科斯特洛综合征的遗传病因
  • 批准号:
    7339043
  • 财政年份:
    2005
  • 资助金额:
    $ 31.47万
  • 项目类别:

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