Airpuff stress phenotype and genetic hypertension

吹气应激表型与遗传性高血压

• 批准号: 6735482
• 负责人: Morton P Printz
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735482
• 关键词: behavioral /social science research tag; cardiovascular function; coping; dietary sodium; environmental stressor; familial hypertension; gene environment interaction; genetic models; genetic strain; genetic susceptibility; heart rate; inbreeding; informatics; laboratory rat; phenotype; quantitative trait loci; startle reaction; stressor; telemetry

Genetic and molecular mechanisms important to the processing of sensory information into abnormal cardiovascular responses remains the focus of this project. We will continue to use the airpuff stress paradigm, which we pioneered for sensori-autonomic processing, as well as restraint and high dietary NaCI stress. Building on our identification of a set of quantitative trait loci (QTL), spread across the genome, which determine cardiovascular and behavioral responses to stressors, we will target specific chromosomal areas to identify candidate genes and potential molecular mechanisms. Our focus remains the SHR model of hypertension using the HXB-BXH set of Recombinant Inbred (RI) rat strains, now rederived into a clean colony in La Jolla, and other strains and congenics. The chromosomal targets of study will be recently identified QTL for (a) the orienting response bradycardia on 2 and 3, (b) airpuff startle elicited tachycardia responses on 1 and 10, and secondarily (c) basal arterial pressure on 8 and airpuff-startle pressor response on 6. We will also study arterial pressor and depressor loci we have identified on 2. Four aims are identified. In aim 1 we will develop and test congenics to narrow the target QTL and seek candidate genes. We will use a novel method along with speed congenic strategies. In aim 2 we will seek to identify candidate genes for the target QTL of Aim 1 by using both specific microarrays and subtractive methods, subtractive suppression hybridization (SSH). In aim 3, we will directly test the Folkow hypothesis with the thesis that specific genes predispose an organism to hypertension upon repeated environmental stress. In aim 4 we will seek QTL for borderline hypertension and salt sensitivity in a new, inbred strain, the WKY/ Ij-tf, using segregating populations and genome scanning. We will use a mixed modality repeated stress paradigm applied to specific RI strains, selected for divergent arterial pressure or heart rate responses, and the WKY/ Ij-tf to test for genetic susceptibility. Our efforts will identify new candidate genes responsible for abnormal cardiovascular response to stressors and test if susceptibility to repeated stress is a viable etiological mechanism operative in genetic hypertension of the rat.

遗传和分子机制对于将感觉信息处理为异常心血管反应很重要。我们将继续使用Airpuff应力范式，我们开创了用于传感自主加工的启示段，以及约束和饮食中的高饮食NACI压力。我们将基于我们识别一组定量性状基因座（QTL），这些定量性状位点（QTL）遍布基因组，这些定量性状基因组确定了对压力源的心血管和行为反应，我们将靶向特定的染色体区域，以鉴定候选基因和潜在的分子机制。我们的重点仍然是使用HXB-BXH的HXB-BXH近近交（RI）大鼠菌株的SHR高血压模型，现在已重新修复为La Jolla的干净菌落，以及其他菌株和凝聚力。研究的染色体靶标将最近 确定了（a）2和3，（b）Airpuff惊吓的QTL的QTL 对1和10的心动过速反应，其次（c）8的基础动脉压，以及6的airpuff启动压力反应。我们还将研究我们在2上确定的动脉压力和降压位点。确定了四个目标。确定了四个目标。在AIM 1中，我们将开发和测试友善者，以缩小目标QTL并寻求候选基因。我们将使用一种新颖的方法以及速度的策略。在AIM 2中，我们将寻求通过使用特定的微阵列和减法方法，减法抑制杂交（SSH）来识别AIM 1目标QTL的候选基因。在AIM 3中，我们将通过以下论点直接检验民间或假设，即特定的基因使生物体在反复的环境压力后易于高血压。在AIM 4中，我们将在新的近交菌株WKY/ IJ-TF中寻求QTL，以使用分离的种群和基因组扫描，以寻求新的近交菌株WKY/ IJ-TF的临界高血压和盐敏感性。我们将使用应用于特定RI菌株的混合方式重复应力范式，选择用于分歧的动脉压或心率反应以及WKY/ IJ-TF来测试遗传易感性。我们的努力将确定新的候选基因对压力源的异常反应，并测试对重复应激的敏感性是否是大鼠遗传性高血压的可行病因机制。