ANGIOTENSINOGEN AND HUMAN HYPERTENSION

描述：(改编自摘要)这是一份修订后的提案，旨在 研究血管紧张素原及其基因或基因突变 蛋白质可能是高血压的易感因素。调查人员已经 检测肾素-血管紧张素系统的基因参与 通过对受影响的兄弟姐妹进行连锁分析发现人类高血压。 在来自犹他州和法国的两大(379对)患者系列中，他们 已经获得了血管紧张素原基因关联的证据 基因(AGT)与高血压显示出共同的关联 与该病相关的基因(T235)的分子变异，并发现 血浆血管紧张素原浓度的显著差异 高血压病患者中AGT基因残基的作用 235.随后，他们报告了类似的与 先兆子痫(或“毒血症”)，一种常见的妊娠期高血压疾病。 这些数据和其他数据支持这样一种假设，即 AGT构成了原发性高血压的遗传性易感基因。 这一假设是续签申请的重点，长期- 获取一些病理生理学线索的术语目标 机械装置。最初，他们定义了四个具体目标：(1)测试 自然产生的错义变体的功能意义 人血管紧张素原的体外诱变及表达 随后进行了物理、生化和代谢分析 重组产品；(2)生产和纯化人血管紧张素原 以适合物理研究的规模；(3)调查 影响底物的系统决定因素 小鼠肾素与小鼠血管紧张素原的反应速率 多肽和体外重组产物作为底物和重组 小鼠肾素作为酶；(4)利用小鼠的同源重组 为了产生增加或减少的转基因动物 血管紧张素原的反应性或表达对未来生理的影响 血管紧张素原在调节中作用的生化研究 血压与高血压发病机制的关系。因为他们的 初步提交后，他们发现了另一种分子变体 发生在转录起始点的-6位置 存在于大多数编码T235的基因中。这一地区是众所周知的 关键影响基础转录速率和 使用血管紧张素原启动子的片段启动 在残基-6处观察到的两个等位基因。

DESCRIPTION: (adapted from the abstract) This is a revised proposal to study angiotensinogen and how mutations of either its gene or protein might predispose to hypertension. The investigators have tested the involvement of genes of the renin-angiotensin system in human hypertension by linkage analysis in pairs of affected siblings. In two large (379 pairs) series of patients form Utah and France, they have obtained evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension, demonstrated association of a common molecular variant of the gene (T235) with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects as a function of AGT genotype at residue 235. Subsequently, they have reported a similar association with preeclampsia (or 'toxemia'), a common hypertensive disorder of pregnancy. These and other data support the hypothesis that molecular variants of AGT constitute inherited predispositions to essential hypertension. This hypothesis is the focus of the renewal application with the long- term objective of obtaining some clues about pathophysiological mechanisms. Initially, they define four specific aims: (1) to test the functional significance of naturally-occurring missense variants of human angiotensinogen through in vitro mutagenesis and expression followed by physical, biochemical, and metabolic analyses of recombinant products; (2) to produce and purify human angiotensinogen on a scale amenable to physical studies; (3) to investigate systematically determinants of the substrate which affect the reaction rate of mouse renin with mouse angiotensinogen, using synthetic peptides and in vitro recombinant products as substrates and recombinant mouse renin as enzyme; (4) to exploit homologous recombination in mice in order to generate transgenic animals with increased or decreased reactivity or expression of angiotensinogen for future physiological and biochemical studies on the role of angiotensinogen in the regulation of blood pressure and the pathogenesis of hypertension. Since their initial submission, they have found that another molecular variant occurring at the -6 position of the transcription start site was present in most genes coding for T235. This region is known to harbor elements that critically affects the basal transcription rate and initiating using segments of the angiotensinogen promoter with each of the two alleles observed at residue -6.