The role of Raf-MEK signaling in the pathogenesis of hypertrophic cardiomyopathy

Raf-MEK信号在肥厚型心肌病发病机制中的作用

基本信息

  • 批准号:
    8707248
  • 负责人:
  • 金额:
    $ 12.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM), a disease characterized by abnormal thickening of the ventricular myocardium, is a common genetic cause of heart failure and sudden death. The prevalence of this condition is 1:500, and over the last twenty years there has been tremendous advancement in understanding the genetic underpinnings of this Mendelian disorder. However, despite the robust genetic knowledge that exists for this disease, the development of novel treatments has been limited. The genes implicated in HCM encode for cardiomyocyte sarcomeric proteins, and select rodent models have been created that model components of the disease process. However, performing a large scale screen for novel therapeutics using mammalian animal models is cost and time prohibitive. Recently, the emergence of the larval zebrafish as a tool for disease modeling and phenotype-driven small molecule screens has provided a viable alternative to mammalian model systems. We recently developed a zebrafish model of a human hypertrophic cardiomyopathy mutation in cardiac Troponin T. A comparison between our zebrafish model and a mouse model of HCM, discovered that the cardiac natriuretic peptide genes, nppa and nppb, were robustly induced in both HCM models. Utilizing this discovery, we created a zebrafish transgenic reporter line that models the pathologic activation of the nppb gene. We then performed a targeted kinase inhibitor screen to identify pathways important in the pathological induction of nppb secondary to hypertrophic stimuli. We discovered that mitogen-activated protein kinase kinase (MEK1/2) was important in the pathological induction of this signaling pathway. This application is focused on investigating the role of the Raf/MEK signaling cascade in the pathophysiology of sarcomeric gene mutations. Aim 1. Determine which components of the Raf-MEK signaling cascade are important in HCM pathophysiology. Utilizing a zebrafish model of a sarcomeric gene mutation, we will test which components of the Raf-MEK signaling cascade are important in activating hypertrophic signaling pathways in vivo. We will target these pathways using a combination of small molecule inhibitors, and genetic knock down techniques. Aim 2. Delineate the effect of selective inhibition of MEK signaling in a mammalian model of HCM. We will determine if pharmacological inhibition of MEK signaling can prevent the development of disease in a mammalian model of hypertrophic cardiomyopathy. Frist, we will determine the developmental timing of when sarcomeric gene mutations initiate the hypertrophic signaling cascade so that we can define a prehypertrophic and hypertrophic interval. We will then selectively target MEK1/2 using a small molecule inhibitor to determine if targeting this kinase can prevent the development of HCM without causing cardiotoxicity. Hypertrophic cardiomyopathy caused by sarcomeric gene mutations is a common inherited cardiovascular condition with no effective methods to prevent the development of disease. We will utilize novel in vivo models to determine if manipulation of the Raf-MEK signaling pathway is an effective method to prevent the development of ventricular hypertrophy caused by sarcomeric gene mutations.
描述(由申请人提供):肥厚型心肌病(HCM)是一种以心肌异常增厚为特征的疾病,是导致心力衰竭和猝死的常见遗传原因。这种疾病的患病率是1:500,在过去的20年里,在理解这种孟德尔疾病的遗传基础方面取得了巨大的进步。然而,尽管对这种疾病存在强大的遗传学知识,但新治疗方法的开发一直受到限制。HCM中涉及的基因编码心肌细胞肌瘤蛋白,并选择啮齿动物模型来模拟疾病过程的组成部分。然而,使用哺乳动物动物模型进行大规模的新疗法筛选成本和时间都是令人望而却步的。最近,斑马鱼幼体的出现为疾病建模和表型驱动的小分子筛选提供了一种可行的替代哺乳动物模型系统的工具。我们最近建立了人类肥厚型心肌病心肌肌钙蛋白T突变的斑马鱼模型。将我们的斑马鱼模型与肥厚性心肌病小鼠模型进行比较,发现在两种肥厚性心肌病模型中,心钠素基因NPPA和NPPB都得到了强有力的诱导。利用这一发现,我们创建了一个斑马鱼转基因报告系,模拟NPPB基因的病理激活。然后,我们进行了一项有针对性的激酶抑制剂筛选,以确定在肥大刺激继发于NPPB的病理诱导中重要的通路。我们发现,丝裂原活化蛋白激酶(MEK1/2)在这一信号通路的病理诱导中起重要作用。这一应用重点是研究Raf/MEK信号级联在肉瘤基因突变的病理生理学中的作用。目的1.确定Raf-MEK信号通路中哪些成分在肥厚性心肌病的病理生理学中起重要作用。利用斑马鱼的肌瘤基因突变模型,我们将测试Raf-MEK信号级联中的哪些组件在体内激活肥大信号通路方面具有重要作用。我们将结合使用小分子抑制剂和基因敲除技术来针对这些途径。目的2.探讨选择性抑制MEK信号转导通路在哺乳动物肥厚性心肌病中的作用。我们将确定在肥厚型心肌病的哺乳动物模型中,药物抑制MEK信号是否可以防止疾病的发展。首先,我们将确定肉瘤基因突变何时启动肥大信号级联的发育时机,以便我们可以定义肥大前期和肥大间隔。然后,我们将使用一种小分子抑制剂选择性地靶向MEK1/2,以确定靶向该激酶是否可以在不引起心脏毒性的情况下防止肥厚性心肌病的发展。肌瘤基因突变引起的肥厚型心肌病是一种常见的遗传性心血管疾病,目前尚无有效的方法预防疾病的发展。我们将利用新的体内模型来确定操纵Raf-MEK信号通路是否是预防由肌瘤基因突变引起的心室肥厚的有效方法。

项目成果

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Jason Becker其他文献

Jason Becker的其他文献

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{{ truncateString('Jason Becker', 18)}}的其他基金

MDM2-HIF signaling in pathological ventricular remodeling
病理性心室重构中的 MDM2-HIF 信号传导
  • 批准号:
    10705352
  • 财政年份:
    2022
  • 资助金额:
    $ 12.54万
  • 项目类别:
Cell State Specific modifiers of pathological cardiac remodeling
病理性心脏重塑的细胞状态特异性调节剂
  • 批准号:
    10186790
  • 财政年份:
    2017
  • 资助金额:
    $ 12.54万
  • 项目类别:
The role of Raf-MEK signaling in the pathogenesis of hypertrophic cardiomyopathy
Raf-MEK信号在肥厚型心肌病发病机制中的作用
  • 批准号:
    9313746
  • 财政年份:
    2013
  • 资助金额:
    $ 12.54万
  • 项目类别:
The role of Raf-MEK signaling in the pathogenesis of hypertrophic cardiomyopathy
Raf-MEK信号在肥厚型心肌病发病机制中的作用
  • 批准号:
    8425850
  • 财政年份:
    2013
  • 资助金额:
    $ 12.54万
  • 项目类别:

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