Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases

发育不良相关动脉疾病的基因组和功能研究

基本信息

  • 批准号:
    10551914
  • 负责人:
  • 金额:
    $ 91.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2029-01-31
  • 项目状态:
    未结题

项目摘要

Project summary Fibromuscular dysplasia (FMD) is a non-atherosclerotic, systemic arteriopathy with excess burden on women. FMD may have varying manifestations, including hypertension, stroke and myocardial infarction, among others, depending on the arterial beds involved by arterial stenosis, aneurysm, dissection or tortuosity. Thus, the clinical diagnosis of FMD encompasses a spectrum of arterial dysplasia phenotypes, and these may be either sporadic or familial. Arterial medial fibrodysplasia underlies the pathologic arterial remodeling and susceptibility to loss of arterial integrity, and genetic susceptibility loci identified thus far implicate arterial smooth muscle and its corresponding extracellular matrix. The genetic architecture of these dysplasia- associated arterial diseases is emerging as variable, with contributions of complex genetic architecture, rare heritable variants in a subset of cases, and potential modifier genes. The proposed studies will comprehensively characterize the genetic and allelic spectrum, and test the hypothesis that the molecular and functional basis of these genetic influences, while operative in a model of locus and allelic heterogeneity, converge upon alterations of the vascular smooth muscle matricellular unit. The goal of this R35 proposal is to precisely define the genetic basis of arterial fibrodysplasia and employ relevant model systems for gene and variant mechanistic testing, resolution of genetic variants of uncertain significance, testing influences of potential modifier genes, and analysis of regulatory mechanisms, particularly those relevant to vascular sex differences. This proposal builds upon strengths in vascular disease characterization, high-throughput genetic and genomic applications, computational analysis, and molecular genetic approaches in model systems. We will conduct high throughput targeted gene sequencing to define the allelic spectrum of the involved genes in our clinical and biorepository resources, followed by hypothesis driven experiments in vascular cell and murine models for in vitro and in vivo definition of the mechanisms of the genetic findings impacting the matricellular components which are altered in arterial fibrodysplasia. The role of biologic sex and factors underlying relevant sex differences in arterial remodeling will be determined across the experiments. The outcome of this R35 and the proposed studies will be the successful integration of genomics and functional studies to provide new insights into the mechanisms of arterial dysplasia. The completion of these studies will provide critical and urgently needed biologic insights that will advance precision health objectives including disease diagnosis, prevention, and treatment, and to reduce the burden of cardiovascular morbidity and mortality.
项目摘要 纤维肌性发育不良(FMD)是一种非动脉粥样硬化性的全身性动脉病,对妇女造成过度负担。 FMD可能有不同的表现,包括高血压,中风和心肌梗死,其中 其他的,取决于动脉狭窄、动脉瘤、夹层或迂曲所涉及的动脉床。因此,在本发明中, FMD的临床诊断包括一系列动脉发育不良表型, 散发性的或家族性的。动脉中膜纤维发育不良是病理性动脉重塑的基础, 动脉完整性丧失的易感性,以及迄今为止发现的涉及动脉 平滑肌及其相应的细胞外基质。这些发育不良的遗传结构- 相关的动脉疾病正在成为变量,与复杂的遗传结构,罕见的贡献, 在一个子集的情况下,遗传变异,和潜在的修饰基因。拟议的研究将 全面表征遗传和等位基因谱,并测试分子和 这些遗传影响的功能基础,虽然在基因座和等位基因异质性模型中起作用, 集中于血管平滑肌基质细胞单位的改变。本R35提案的目标是 精确定义动脉纤维发育不良的遗传基础,并采用相关的基因和 变异机制检测,不确定意义的遗传变异的分辨率, 潜在的修饰基因,以及调控机制的分析,特别是那些与血管性别相关的基因 差异该提案建立在血管疾病表征、高通量遗传学和基因治疗方面的优势之上。 以及模型系统中的基因组应用、计算分析和分子遗传学方法。我们 将进行高通量靶向基因测序,以确定相关基因的等位基因谱 我们的临床和生物资源,其次是假设驱动的实验,在血管细胞和小鼠 用于体外和体内定义影响基质细胞的遗传发现机制的模型 在动脉纤维发育不良中改变的成分。生物性别的作用及相关因素 将在整个实验中确定动脉重塑的性别差异。这一R35的结果和 拟议的研究将是基因组学和功能研究的成功整合, 深入了解动脉发育不良的机制。这些研究的完成将提供关键和 迫切需要的生物学见解,将推进精确的健康目标,包括疾病诊断, 预防和治疗,并减少心血管疾病发病率和死亡率的负担。

项目成果

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SANTHI K GANESH其他文献

SANTHI K GANESH的其他文献

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{{ truncateString('SANTHI K GANESH', 18)}}的其他基金

Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases
发育不良相关动脉疾病的基因组和功能研究
  • 批准号:
    10349917
  • 财政年份:
    2022
  • 资助金额:
    $ 91.36万
  • 项目类别:
Genetics of Vascular Remodeling
血管重塑的遗传学
  • 批准号:
    8117567
  • 财政年份:
    2010
  • 资助金额:
    $ 91.36万
  • 项目类别:
Genetics of Vascular Remodeling
血管重塑的遗传学
  • 批准号:
    8302309
  • 财政年份:
    2010
  • 资助金额:
    $ 91.36万
  • 项目类别:
Genetics of Vascular Remodeling
血管重塑的遗传学
  • 批准号:
    8037290
  • 财政年份:
    2010
  • 资助金额:
    $ 91.36万
  • 项目类别:

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