Animal Models for Studying the Genetics of Hypertension

描述（由申请人提供）：本续中提出的研究的长期目标仍然是帮助解开原发性高血压的遗传复杂性。对于即将到来的资助期，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，包括对编码肾素（Ren-1）、醛固酮合成酶（Cyp11b2）、肾上腺髓质素（Adm）及其受体（Ca/cr1）的基因进行滴定。降钙素受体类受体。将测定血压，并使用定量RT-PCR来评估诱导体内平衡代偿的程度。环境变化的影响，如饮食盐和怀孕，将被调查。我们的期望是，如果这些基因的表达因人类遗传多态性而发生变化，那么这些分析将识别出其他基因，这些基因被预测会导致血压或血压稳态的变化。特定目标（ii）将探索一个新的问题——在同一生理系统（例如Agt和Agtr1a）和不同系统（例如Agt和Npr1）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。我们将培育现有的动物，为每对基因提供四种组合（高与高，高与低，低与高和低与低）。我们将开发计算机模拟，包括不同系统之间的相互作用，并将它们与实验数据进行比较。发现的不足之处将有助于模型的改进。这种来回的过程有望大大增加目前对为什么某些遗传变异组合有害而其他遗传变异组合有益的理解。具体目标（iii）将调查我们发现的高度显著的性别相关差异背后的机制(a)与血压控制相关的10多个基因的表达和反应；(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Agtr1a和编码激肽激酶基因Kiki的表达之间的关系。所有这三种性别影响都与人类直接相关，我们期望他们的分析将揭示一些以前未知的原因，这些原因可能导致男性和绝经前女性心血管风险因素的差异。

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.