Animal Models for Studying the Genetics of Hypertension

描述(由申请人提供)：这项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间，我们选择了三个目标：特定目标(I)将完成或扩展我们的定量分析，以包括以下编码基因的滴定：肾素(REN-1)、醛固酮合成酶(Cyp11b2)、肾上腺髓质素(Adm)及其受体(Ca/CR1)。降钙素受体样受体。血压将被测定，定量RT-PCR将被用来评估体内平衡补偿已被诱导的程度。将调查环境变化的影响，如饮食盐分和怀孕。我们的期望是，这些分析将识别更多的基因，如果它们的表达因人类遗传多态而发生变化，那么它们将导致血压或血压稳态的变化。特定的目标(Ii)将探索一个新的问题--如何通过在相同的生理系统(例如AGT和Agtr1a)和不同的系统(例如AGT和Npr1)中结合高表达和低表达的基因变异来影响血压及其稳态。我们将培育目前可用的动物，为每对基因提供四种组合(高和高、高和低、低和高以及低和低)。我们将开发包括不同系统之间相互作用的计算机模拟，并将它们与实验数据进行比较。任何暴露的不足之处都将有助于模型的改进。这一往返过程预计将极大地提高目前对某些遗传变异组合是有害的，而另一些是有益的理解。具体目的(Iii)将调查导致高度显著性别差异的机制，我们已经发现：(A)与血压控制有关的10多个基因的表达和反应；(B)血压与AGT肝脏表达变化的关系，这些变化与基因拷贝数无关；以及(C)Agtr1a和Kiki肾脏表达之间的关系。Kiki是编码激肽释放酶的基因。所有这三种性别影响都与人类直接相关，我们预计他们的分析将揭示男性和绝经前女性心血管风险因素差异背后的一些以前不为人知的原因。

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.