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

基本信息

批准号：
8484427
负责人：
NELSON RUIZ-OPAZO
金额：
$ 38.29万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484427
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

项目摘要

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.

描述（由申请人提供）：我们的长期目标是阐明基本或多基因高血压的病因，重点是阐明遗传变异的遗传变异，这些变异构成了高血压易感性和基因环境相互作用，从而加剧了高血压的易感性和最终轨道疾病。在临床研究中，在脉冲波速度或PWV中测量的动脉僵硬的新兴重要性表明，增加的PWV和心血管结局（中风，冠心病和慢性肾脏疾病）的相关性已引起了可能的可靠预测参数，但同时突显了对动物模型研究的需求。因此，该研究建议的重点是RFA提出的目标：＃1）“探索动脉僵硬与动物模型中高血压的发展之间的时间关系”，以及＃2），以进行“细胞和分子研究，这些机制导致导致管道动脉在（基本/多基因）高血压的上下文中僵化的机制”。为此，我们优先考虑以下具体目的：目标1。检查大动脉僵硬之间的时间关系（以主动脉PWV和劳累的菌株，颈动脉PWV和高分辨率超声检查）以及盐对盐敏感性高血压的发展（通过非压力24/7/7远程远程BP的SBP，DBP，DBP，DBP，DBP，DBP，DBP，DBP，DEMET）的时间关系。达尔的老鼠。 AIM 2。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，以及假定的基因表达变化，这是NA诱导的沿高血压及其最终器官并发性疾病过程的NA引起的动脉刚度的加重和进展。目的3。通过F2的全基因组扫描[Dahl S X Dahl R] - 男性和雌性大鼠识别常见和性别特异性的定量性质（QTLS），通过f2 [dahl s x dahl r]通过基因组范围的扫描来阐明遗传机制在动脉刚度的因果中的作用。总而言之，这三个目标将阐明主动脉和颈动脉刚度与NA诱导的可触摸性高血压大鼠模型中的多基因（必需）高血压和中风的关系，并深入了解因果细胞，分子，分子和遗传机制。