Genetic mechanisms of arterial stiffness in polygenic salt-sensitive hypertension

多基因盐敏感性高血压动脉僵硬度的遗传机制

• 批准号: 8292163
• 负责人: NELSON RUIZ-OPAZO
• 金额: $ 40.22万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292163
• 关键词: Address; Age; Animal Model; Arteries; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Chronic Kidney Failure; Clinical Research; Collagen; Coronary heart disease; Data; Development; Disease; Elastin; Environment; Epigenetic Process; Essential Hypertension; Etiology; Female; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Goals; Housing; Hypertension; Implant; Intervention; Investigation; Lead; Life; Measurement; Measures; Modeling; Molecular; Molecular Genetics; Monitor; Organ; Outcome; Pathway interactions; Physiologic pulse; Play; Predisposition; Prevention strategy; Quantitative Trait Loci; Rattus; Research; Research Proposals; Resistance; Resolution; Risk; Role; Sodium Chloride; Stroke; Structure; Susceptibility Gene; System; Testing; Time; Transgenic Organisms; Ultrasonography; Work; arterial stiffness; experience; gene environment interaction; genetic linkage analysis; genetic variant; genome wide association study; genome-wide linkage; insight; male; meetings; miniaturize; nano; new technology; public health relevance; salt sensitive; sex; systems research; trait

DESCRIPTION (provided by applicant): Our long term goal is to elucidate the etiology of essential or polygenic hypertension with a focus on the elucidation of genetic variants that underlie hypertension susceptibility and gene-environment interactions which exacerbate hypertension susceptibility and end-organ disease. The emerging importance of arterial stiffening measured as pulse wave velocity or PWV in clinical studies demonstrating the association of increased PWV and cardiovascular outcomes (stroke, coronary heart disease, and chronic kidney disease) has pinpointed a likely robust predictive parameter, but at the same time highlighted the need for animal model studies to address mechanisms. Accordingly, this research proposal focuses on RFA-stated goals: #1) "to explore the temporal relationship between arterial stiffening and the development of hypertension in an animal model", and #2) to conduct "cellular and molecular investigation of mechanisms that lead to conduit artery stiffening in the context of (essential/polygenic) hypertension". To accomplish this we have prioritized the following specific aims: Aim 1. Examine the temporal relation between large artery stiffening (measured as aortic PWV and strain, carotid PWV and strain via high-resolution ultrasonography), and the development of salt-sensitive hypertension (measured via non-stress 24/7 telemetric BP analysis of SBP, DBP, MAP and PP) and stroke in both male and female stroke-prone Dahl S rats. Aim 2. Define the temporal and spatial changes in aortic and carotid artery structure in all three vessel layers, along with putative gene expression changes that underlie Na-induced exacerbation and progression of arterial stiffness along the disease course of hypertension and its end-organ complications. Aim 3. Elucidate the role of genetic mechanisms in the causation of arterial stiffness in the context of polygenic salt-sensitive hypertension via genome-wide scan of F2[Dahl S x Dahl R]-intercross male and female rats identifying common and sex-specific quantitative trait loci (QTLs) that contribute to arterial stiffness individually or interactively. Altogether, these three aims will elucidate the relationship of aortic and carotid arterial stiffness to polygenic (essential) hypertension and stroke in a Na-induced stroke-prone hypertension rat model, as well as give insight into causal cellular, molecular, and genetic mechanisms. PUBLIC HEALTH RELEVANCE: The emerging importance of arterial stiffening in clinical studies demonstrating the association of increased arterial stiffness and cardiovascular diseases like hypertension, stroke, coronary heart disease, and chronic kidney disease, has pinpointed a likely robust predictive parameter of these diseases. Accordingly, our research will help to elucidate the relationship of arterial stiffness to hypertension and give insight into causal mechanisms of abnormal arterial stiffness. This information will help to establish new intervention and prevention strategies for essential hypertension and its associated target organ complications like stroke, coronary heart disease, and chronic kidney disease.

描述（由申请人提供）：我们的长期目标是阐明原发性或多基因高血压的病因，重点是阐明高血压易感性的遗传变异和加剧高血压易感性和终末器官疾病的基因-环境相互作用。在临床研究中，以脉搏波速度或PWV测量的动脉硬化的重要性日益显现，证明了PWV增加与心血管结局（卒中、冠心病和慢性肾病）的相关性，这已经确定了一个可能的稳健预测参数，但同时强调了动物模型研究解决机制的必要性。因此，本研究提案侧重于RFA规定的目标：#1）“探索动物模型中动脉硬化与高血压发展之间的时间关系”，以及#2）进行“在（原发性/多基因）高血压背景下导致管道动脉硬化的机制的细胞和分子研究”。为了实现这一目标，我们优先考虑了以下具体目标：目标1。检查大动脉硬化（通过高分辨率超声检查测量为主动脉PWV和应变，颈动脉PWV和应变）与盐敏感性高血压（通过SBP，DBP，MAP和PP的非应激24/7遥测BP分析测量）和卒中之间的时间关系，在雄性和雌性卒中易感Dahl S大鼠中。目标二。定义所有三个血管层中主动脉和颈动脉结构的时间和空间变化，沿着假定的基因表达变化，这些变化是钠诱导的动脉僵硬度恶化和进展的基础，沿着高血压及其终末器官并发症的病程。目标3。通过对F2代[Dahl S x Dahl R]杂交雄性和雌性大鼠进行全基因组扫描，确定单独或交互作用导致动脉僵硬度的常见和性别特异性数量性状位点（QTL），阐明遗传机制在多基因盐敏感性高血压背景下动脉僵硬度病因中的作用。总之，这三个目标将阐明主动脉和颈动脉僵硬度的关系，多基因（原发性）高血压和中风在钠诱导的中风倾向的高血压大鼠模型，以及深入了解因果细胞，分子和遗传机制。 公共卫生相关性：在临床研究中，动脉硬化的重要性日益显现，证明了动脉硬化增加与心血管疾病（如高血压、中风、冠心病和慢性肾病）的相关性，这已经确定了这些疾病的一个可能的稳健预测参数。因此，我们的研究将有助于阐明动脉僵硬度与高血压的关系，并深入了解异常动脉僵硬度的因果机制。这些信息将有助于建立新的干预和预防策略，原发性高血压及其相关的靶器官并发症，如中风，冠心病和慢性肾脏疾病。