MODELS FOR STUDYING THE GENETICS OF HYPERTENSION

这项续期申请的目的是继续在 上一个供资期间侧重于分析各种机构的作用 高血压候选基因的剂量调控 在转基因小鼠身上。这项先前的工作涉及使用基因 目标是创建具有0、1、2、3和4个副本的小鼠 候选基因定位于它们的正常染色体位置，然后 评估这些明确变化对高血压患者的影响 老鼠。研究表明，基因剂量决定了 这些直接影响血液的基因的表达 血压，或由于动态平衡对血压有钝化影响 由其他遗传因素介导的调节。当时的假设是 从这些先前的研究中发展而来，并将在 建议的研究是，一种基因表达水平的变化 多种基因会导致血压变化，这可能是一种 反映了被操纵的基因的表达增加，或者可能是 钝化或完全遗漏取决于内环境平衡调整 受其他因素的影响。Smithies博士解释了这些迟钝的变化 由于自动态平衡调整以来虚拟血压发生变化(即) 其他感知血液的非操纵基因改变了慢性表达 压力变化)，这可以被证明导致不存在 可检测到的血压变化。这一假说及其启示 因为高血压的遗传学将由申请者在五年内进行测试 明确的目标。前四个目标将调查对血液的影响 4个候选基因表达变化的压力：1)肾素1C 基因2)Agtr1a基因3)A型利钠肽受体基因4) 利钠肽“清除”型受体基因。 最终的具体目标包括开发路径图 展示了目标1-4中这些遗传决定因素的相互作用。 这包括预测和使用以下工具测试这些预测 为这些研究产生的小鼠之间的杂交。

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.