BIOCHEMISTRY AND GENETICS OF HYPERTENSION

我的长期目标是用生物化学和遗传学术语来定义 影响血压的基因和评估 这些基因对血压的交互作用。助学金 有三个部分：a)心钠素的研究 (ANF)；b)共分离分析；c)基因组DNA研究。 对ANF的研究将调查肾脏为什么 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，反应迟钝 与近交系Dahl耐盐(R/JR)大鼠进行比较。ANF 受体和细胞受体后事件将被表征 在Dahl大鼠身上。肾脏对心钠素生理水平的反应 膜转运、肾功能试验和血管扩张 将在Dahl大鼠身上评估反应。S/JR大鼠也有 心房心钠素含量高于R/Jr，这可能是 基因介导的。心肺制剂中的心钠素释放 在不同的预负荷、后负荷和胞外条件下 (NA)将确定是否存在ANF释放异常 达尔大鼠。Dahl大鼠心房ANF的mRNA将被 在各种刺激下进行量化，以确定是否存在 心钠素在信使核糖核酸水平的调节异常。 将使用协同隔离分析来确定观察到的标记是否 S/JR与R/JR大鼠肾上腺肾素水平的差异是有因果关系的 与血压差有关。此外，上的交互 已知影响血压的特定基因的血压 在大鼠(Hyp-L、Hyp-2、ES 4)中，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 11β/18，降钙素，肾素，血管紧张素， 降钙素基因相关肽，神经肽Y)将进行比较 检测S/JR和R/JR大鼠基因组水平的突变。 这些已知基因将从黄瓜基因组DNA文库中获得 S/JR和R/JR大鼠使用寡核苷酸探针，这些基因将 通过杂交技术在菌株之间进行比较， 序列测定凝胶电泳法，限制性片段 长度多态和碱基测序。任何DNA多态 发现S/JR和S/JR之间的毒株将进行因果关系测试 与品系间血压差的关系 共同隔离分析。

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.