The Role of Mitochondrial Genes in Hypertension

线粒体基因在高血压中的作用

• 批准号: 6631552
• 负责人: FAINA SCHWARTZ
• 金额: $ 29.02万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631552
• 关键词: African American; biotechnology; cardiovascular disorder epidemiology; caucasian American; family genetics; genetic mapping; human data; human genetic material tag; human middle age (35-64); human old age (65+); hypertension; mitochondrial DNA; mitochondrial disease /disorder; racial /ethnic difference

DESCRIPTION (Verbatim from the application): The aim of this proposal is to assess the contribution of the mitochondrial genome to hypertension (HTN). HTN is a major health problem in the US that affects nearly 20 percent of Americans, and constitutes one of the principal risk factors for stroke, myocardial infarction, and end-stage renal disease. HTN is a complex multifactorial disorder resulting from cumulative effects of multiple environmental and genetic factors. Despite recent progress in molecular characterization of HTN, the number and identity of underlying genes remain poorly understood. To date, the search of genetic determinants of HTN has been focused on the nuclear genome, whereas the role of the mitochondrial genome, present in multiple copies in every cell in every tissue, has not been ascertained. Given recent results of genetic studies that evidence excess maternal inheritance of HTN in Caucasians and African Americans; the age-related clinical manifestations of HTN and the importance of mitochondria in the process of aging; the identification of mitochondrial DNA (mtDNA) mutations underlying various common disorders, including diabetes and several cardiovascular diseases; we hypothesize that mitochondnal genome contributes to etiology of HTN. To test this hypothesis, we propose three specific aims. 1) We will conduct, for the first time, a systematic and extended screening of hypertensive individuals to identify potentially pathogenic mtDNA mutations. 2) Case-control association studies will be conducted to ascertain relevance of the identified mutations to HTN. 3) Functional consequences of specific mtDNA variants will be evaluated by biochemical and metabolic assays of cybrids generated with patients' mitochondria. We will employ modern, high throughput molecular genetic technologies, such as robotic workstations, ABI377 automated sequencer, and mass spectrometry, to assist in mutation identification. Use of such technology will be critical given the large number of subjects to be evaluated. Success of this project has high likelihood to provide a new dimension in HTN research, permit preclinical identification of susceptible individuals, lead to new therapies directed toward specific underlying abnormalities, and development of animal models to test them. This project is designed to interact with an ongoing Hypertension SCOR at Boston University. We will pursue a new line of inquiry into the genetics of HTN utilizing unparalleled patient resources of the present SCOR that include over 1500 blood samples and family history and clinical information from multi-generation families, sib-pairs, and isolated hypertensive cases and normotensive controls, ascertained at FITN clinics associated with Boston Medical Center; as well as expertise of uniquely qualified clinicians, epidemiologists and geneticists.

描述（逐字从应用程序中）：该提案的目的是 评估线粒体基因组对高血压（HTN）的贡献。 htn 在美国是一个主要的健康问题，影响了近20％ 美国人，构成中风的主要风险因素之一， 心肌梗塞和终末期肾脏疾病。 HTN是一个复杂的 由多重影响产生的多因素疾病 环境和遗传因素。尽管最近的分子进展 HTN的表征，潜在基因的数量和身份仍然存在 理解不佳。 迄今为止，对HTN的遗传决定因素的搜索一直集中在 核基因组，而线粒体基因组的作用， 尚未确定每个组织中每个细胞的多个副本。 鉴于遗传研究的最新结果证明了过多的母亲 HTN在高加索人和非裔美国人中的继承；与年龄有关的 HTN的临床表现和线粒体在 衰老过程；线粒体DNA（mtDNA）突变的鉴定 各种普通疾病的潜在疾病，包括糖尿病和几种 心血管疾病；我们假设线粒体基因组有助于 HTN的病因。 为了检验这一假设，我们提出了三个具体目标。 1）我们将进行， 首次进行高血压的系统和扩展筛查 个体鉴定潜在的致病性mtDNA突变。 2）案例对照 将进行关联研究以确定已确定的相关性 HTN突变。 3）特定mtDNA变体的功能后果将是 通过生成的生物化学和代谢测定法评估与 患者的线粒体。我们将采用现代的高通量分子 基因技术，例如机器人工作站，ABI377自动测序仪， 和质谱法，以帮助突变鉴定。使用这种使用 鉴于要评估大量受试者，技术将是至关重要的。 该项目的成功很有可能在HTN中提供新的维度 研究，允许对易感人群的临床前识别，导致 针对特定潜在异常的新疗法，并 开发动物模型来测试它们。 该项目旨在与正在进行的高血压得分互动 波士顿大学。我们将追求对遗传学的新调查。 HTN利用当前SCOR的无与伦比的患者资源包括 超过1500种血液样本以及家族史和临床信息 多代家族，同胞对和孤立的高血压病例以及 与波士顿相关的FITN诊所确定的正常控制 医疗中心；以及独特合格临床医生的专业知识， 流行病学家和遗传学家。