Animal Models for Studying the Genetics of Hypertension

描述（由申请人提供）：本延续研究的长期目标仍然是帮助揭示原发性高血压的遗传复杂性。在即将到来的资助期内，我们选择了三个目标：具体目标（i）将完成或扩展我们的定量分析，包括编码以下基因的滴定：肾素（Ren-1），醛固酮合成酶（Cyp 11b 2），肾上腺髓质素（Adm）及其受体（Ca/cr 1）。降钙素受体样受体。将测定血压，并使用定量RT-PCR评估诱导稳态代偿的程度。将调查环境变化的影响，如饮食中的盐和怀孕。我们的期望是，这些分析将确定预测引起血压或其稳态变化的其他基因，如果它们的表达作为人类遗传多态性的结果而变化的话。具体目标（ii）将探索一个新的问题--在同一生理系统中，高表达和低表达的遗传变异是如何影响血压及其稳态的（例如Agt & Agtr 1a）和不同系统（例如Agt & Npr 1）。我们将培育现有的动物，为每对基因提供四种组合（高和高，高和低，低和高，低和低）。我们将开发包括不同系统之间相互作用的计算机模拟，并将其与实验数据进行比较。任何不足之处将有助于改进模型。这个来回的过程预计将大大增加目前的理解，为什么一些组合的遗传变异是有害的和其他有益的。具体目标（iii）将调查的机制，高度显着的性别相关的差异，我们已经发现发生（a）在表达和反应的10多个基因有关的控制血压;（B）血压与肝脏中与基因拷贝数无关的Agt表达变化之间的关系，以及（c）肾脏中Agtr 1 a表达与编码激肽释放酶的基因Kiki之间的关系。所有这三种性别效应都与人类直接相关，我们预计他们的分析将揭示男性和绝经前女性心血管危险因素差异的一些以前未知的原因。

DESCRIPTION (provided by applicant): The long term objective of the research proposed in this continuation remains to help unravel the genetic complexities of essential hypertension. For the coming grant period, we have chosen three aims:Specific aim (i) will complete or extend our quantitative analyses to include titrations of the genes coding for: renin (Ren-1), aldosterone synthase (Cyp11b2), adrenomedullin (Adm) and its receptor (Ca/cr1). the calcitonin receptor like receptor. Blood pressures will be determined and quantitative RT-PCR will be used to assess the degree to which homeostatic compensations have been induced. The effects of environmental changes, such as dietary salt and pregnancy, will be investigated. Our expectation is that these analyses will identify additional genes predicted to cause changes in blood pressure or its homeostasis if their expression varies as a result of genetic polymorphisms in humans.Specific aim (ii) will explore a new problem--how blood pressure and its homeostasis are affected by combining high expressing and low expressing genetic variants within the same physiologic system (for example Agt & Agtr1a) and in different systems (for example Agt & Npr1). We will breed currently available animals to give four combinations (high & high, high & low, low & high and low & low) for each pair of genes. We will develop computer simulations that include interactions between different systems, and will compare them with experimental data. Any inadequacies revealed will facilitate improvement of the models. This to-and-fro process is expected to greatly increase current understanding of why some combinations of genetic variations are detrimental and others beneficial.Specific aim (iii) will investigate the mechanisms underlying highly significant gender-related differences that we have found occur (a) in the expression and responses of more than 10 genes related to the control of blood pressure; (b) in the relationship between blood pressure and variations in the liver expression of Agt that are unrelated to gene copy number, and (c) between kidney expression of Agtr1a and Kiki, the gene coding for kallikrein. All three of these gender effects have direct relevance to humans, and we expect that their analysis will reveal some previously unknown causes underlying the differences in cardiovascular risk factors in males and pre-menopausal females.