BIOCHEMISTRY AND GENETICS OF HYPERTENSION

我的长期目标是从生物化学和遗传学的角度 影响血压的基因， 这些基因对血压的相互作用。 授出 有三个组成部分：a）对心房利钠因子的研究 (ANF)B）共分离分析; ANF的研究将调查肾脏 的近交系Dahl盐敏感（S/JR）大鼠对ANF反应低下 与近交系Dahl盐敏感（S/JR）大鼠相比， 与近交系Dahl耐盐（R/JR）大鼠相比， ANF 受体和细胞后受体事件将被表征 在达尔鼠体内 生理水平心钠素的肾脏反应 膜转运、肾功能试验和血管舒张试验 将在Dahl大鼠中评价反应。 S/JR大鼠也有 心房ANF含量高于R/JR，这可能是 基因介导的 心钠素从心肺制剂中的释放 在不同的前负荷、后负荷和细胞外条件下， (Na)将确定是否存在ANF释放的任何异常， 达尔老鼠。 来自Dahl大鼠心房的ANF的mRNA将被 在各种刺激下定量，以确定是否存在任何 ANF在mRNA水平的调控异常。 共分离分析将用于确定观察到的是否显著 S/JR与R/JR大鼠肾上腺肾素的差异是因果关系 与血压差异有关。 同时， 已知影响血压的特定基因的血压 在大鼠中（Hyp-1、Hyp-2、Es 4），将在遗传学上确定 实验 最后，编码高血压相关分子的基因 (ANF细胞色素P450 11 β/18，降钙素，肾素，血管紧张素， 降钙素基因相关肽，神经肽Y）进行比较 S/JR和R/JR大鼠基因组DNA水平的突变。 这些已知的基因将从基因组DNA文库中获得， S/JR和R/JR大鼠，并将基因 通过交叉杂交技术在菌株之间进行比较， 序列测定凝胶电泳，限制性片段 长度多态性和碱基测序。 任何DNA多态性 将检测S/JR和S/JR菌株之间的因果关系 与菌株之间血压差异的关系， 共分离分析

My longterm objective is to define in biochemical and genetic terms the genes which influence blood pressure and to evaluate the interactive effects of these genes on blood pressure. The grant has three components: a) studies on atrial natriuretic factor (ANF); b) cosegregation analysis; c) studies on genomic DNA. Studies on ANF will investigate possible reasons why the kidneys of inbred Dahl salt-sensitive (S/JR) rats are hyporesponsive to ANF compared to inbred Dahl salt-sensitive (S/JR) rats hyporesponsive to ANF compared to inbred Dahl salt-resistant (R/JR) rats. ANF receptors and cellular post-receptor events will be characterized in Dahl rats. Renal responses to ANF at the physiological level of membrane transport, renal functional tests and vasodilatory responses will be evaluated in Dahl rats. S/JR rats also have higher atrial ANF content then R/JR, and this is probably genetically mediated. ANF release from heart-lung preparations under varying conditions of preload, after load and extracellular (Na) will determine if there is any abnormality of ANF release in Dahl rats. mRNA for ANF from atria of Dahl rats will be quantitated under a variety of stimuli to determine if there is any abnormality of ANF regulation at the mRNA step. Cosegregation analysis will be used to determine if observed marked differences in adrenal renin in S/JR vs R/JR rats are causally related to blood pressure differences. Also the interactions on blood pressure of specific genes known to influence blood pressure in the rat (Hyp-l, Hyp-2, Es 4), will be determined in genetic experiments. Lastly, genes that code for molecules of interest in hypertension (ANF, cytochrome P450 11 beta/18, calcitonin, renin, angiotensin, calcitonin-gene-related peptide, neuropetide Y) will be compared for mutations at the genomic DNA level in S/JR and R/JR rats. These known genes will be obtained from genomic DNA libraries of S/JR and R/JR rats using oligonucleotide probes, and the genes will be compared between strains by cross hybridization techniques, sequence-determined gel electrophoresis, restriction fragment length polymorphisms, and base sequencing. Any DNA polymorphisms found between S/JR and S/JR strains will be tested for a causal relationship to the blood pressure differences between strains by cosegregation analysis.