MODELS FOR STUDYING THE GENETICS OF HYPERTENSION

此更新申请的目的是继续在 上一个供资期的重点是分析各种机构的作用， 高血压的候选基因通过操纵它们的剂量 在基因工程小鼠中。 这项先前的工作涉及使用基因 靶向创建具有零、一、二、三和四个拷贝的 候选基因靶向其正常染色体位置，然后 评估这些定义的改变对高血压的影响， 老鼠. 研究表明，基因剂量决定了 这些基因的表达直接影响血液 压力，或由于体内平衡而对血压产生钝化作用 由其他遗传因素介导的调节。 假设是， 从这些先前的研究中开发出来，并将在 提出的研究是，在表达水平的变化， 多种基因会导致血压变化，这可能是一个 这反映了被操纵基因的表达增加，或者可能是 根据体内平衡的调整， 由其他元素组成。 史密斯博士解释说， 由于自稳态调节（即， 通过其他非操纵的感受血液的基因改变慢性表达 压力变化），这可以证明导致缺乏 可检测的血压变化。 这一假设及其含义 高血压的遗传学将由申请人在五个测试 具体目标。 前四个目标将研究对血液的影响 4个候选基因表达改变的压力：1）肾素1C 基因2）Agtr 1A基因3）A型利钠肽受体基因4） 利钠肽“清除”型受体基因。 最后的具体目标涉及发展的路径图 显示目标1-4中这些遗传决定因素的相互作用。 这包括预测以及使用 在这些研究中产生的小鼠之间进行杂交。

The objective of this renewal application is to continue work begun during the prior funding period focused on the analysis of the role of various candidate genes in hypertension through the manipulation of their dosage in genetically engineered mice. This prior work involved using gene targeting to create mice with zero, one, two, three, and four copies of candidate genes targeted at their normal chromosomal locations and then assessing the impact of these defined alterations on hypertension in the mouse. The studies demonstrated that gene dosage determines the levels of expression of these genes which either directly impacted on blood pressure, or had blunted effects on blood pressure due to homeostatic adjustments mediated by other genetic elements. The hypothesis that was developed from these prior studies and which is to be tested in the proposed studies are that variations in the level of expression of a variety of genes will lead to blood pressure changes that may be a reflection of increased expression of the manipulated genes or may be blunted or completely missed depending on the homeostatic adjustments mediated by other elements. Dr. Smithies interprets these blunted changes as virtual blood pressure changes since homeostatic adjustments (i.e.) altered chronic expression by other non-manipulated genes sensing blood pressure changes) which can be demonstrated result in an absence of detectable blood pressure changes. This hypothesis and its implications for the genetics of hypertension will be tested by the applicant in five specific aims. The first four aims will investigate the effects on blood pressure of altered expression of f our candidate genes: 1) the renin 1C gene 2) the Agtr1A gene 3) the type A natriuretic peptide receptor gene 4) the natriuretic peptide "clearance" type receptor gene. The final specific aim involves the development of a path diagram displaying the interaction of these genetic determinants from Aims 1-4. This includes predictions and the testing of these predictions using crosses between the mice generated for these studies.