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：
SANTHI K GANESH
金额：
$ 91.36万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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

来源：
https://reporter.nih.gov/project-details/10551914
关键词：
Alleles Aneurysm Arterial Disorder Beds Biological Biological Factors Biological Models Blood Vessels Cardiovascular Manifestation Cardiovascular system Cell model Cessation of life Clinical Complex Computer Analysis Disease Dissection Dysplasia Extracellular Matrix Fibromuscular Dysplasia Genes Genetic Genetic Predisposition to Disease Genomics Goals Growth Heritability Heterogeneity Hypertension Laboratories Medial Modeling Molecular Molecular Genetics Morbidity - disease rate Myocardial Infarction Outcome Pathologic Phenotype Population Precision Health Predisposition Prevention Resolution Resources Role Sex Differences Smooth Muscle Stenosis Stroke Susceptibility Gene Testing Variant Vascular Diseases Vascular Smooth Muscle Woman arterial remodeling biobank biological sex clinical diagnosis disease diagnosis experimental study genetic approach genetic architecture genetic variant in vitro Model in vivo insight mortality mouse model novel diagnostics novel therapeutic intervention variant of unknown significance

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.

项目摘要纤维肌肉发育不良（FMD）是一种非动脉粥样硬化的全身性动脉炎，女性负担过多。 FMD可能具有不同的表现，包括高血压，中风和心肌梗塞其他的，取决于动脉狭窄，动脉瘤，解剖或曲折所涉及的动脉床。因此， FMD的临床诊断涵盖了各种动脉异常发育不良表型，这些可能是零星或家族性。动脉内侧纤维扩展是病理动脉重塑的基础迄今为止确定的动脉完整性丧失和遗传敏感性基因座的敏感性暗示了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 - 相关的动脉疾病已成为可变的，具有复杂遗传结构的贡献，罕见在一部分病例和潜在的修饰基因中，可遗传的变体。拟议的研究将全面地表征了遗传和等位基因光谱，并检验了分子和分子的假设这些遗传影响的功能基础，而在基因座和等位基因异质性模型中的操作，随着血管平滑肌母细胞单元的改变而收敛。该R35建议的目标是精确定义动脉纤维肿瘤的遗传基础，并采用相关的基因模型系统变异机械测试，不确定意义的遗传变异的分辨率，测试影响潜在的修饰基因和调节机制的分析，尤其是与血管性别相关的机制差异。该提案以血管疾病表征，高通量遗传的优势为基础以及模型系统中的基因组应用，计算分析和分子遗传方法。我们将进行高吞吐量的靶向基因测序，以定义涉及基因的等位基因谱我们的临床和生物座席资源，然后是假设驱动的血管细胞和鼠的实验体外和体内的模型定义遗传发现的机理的模型在动脉纤维浮肿中改变的成分。生物性别和相关因素的作用在整个实验中将确定动脉重塑的性别差异。该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以提供新的洞悉动脉发育不良的机制。这些研究的完成将提供至关重要的迫切需要的生物学见解将促进精确的健康目标，包括疾病诊断，预防和治疗，并减轻心血管发病率和死亡率的负担。