Genetic & Physiological Basis of Salt-sensitive Hypertension

描述(由申请人提供)：本PPG的目标是促进我们对一组基因的复杂调控和相互作用的理解，这些基因位于CHR 13的两个不同区域，但在很大程度上，它们共同导致盐敏感性(SS)大鼠的盐源性高血压、肾脏损伤和微循环的血管/血管生成。这些研究旨在探索基因多态如何转化为细胞、组织、器官和整个动物的综合功能。项目1假设CHR 13基因同源区域内的一个或多个基因的序列变异改变了影响SS大鼠延髓粗大升支(MTAL)功能的分子调控网络，并有助于盐敏感型高血压和肾脏损伤的发生。这将通过：1)产生完整注释该同源区域的完成水平的基因组序列；2)通过构建mTAL上皮细胞的分子和生理调控网络，并识别可能导致高血压和肾脏损伤的途径和基因；以及3)通过研究移除或过度表达转录组/蛋白质组/代谢组相关网络中的重要基因的影响。项目2将检验一个新的假设，即非蛋白质编码基因可能在高血压和相关组织损伤中发挥重要作用。我们假设miR-214在盐敏感型高血压和肾损伤的发生发展中起作用，并检测：1)肾脏内microRNA的功能贡献；2)研究其影响的下游机制，研究上游反式和顺式机制；以及3)开展miR-214在人类盐敏感型高血压和肾脏损伤中的初步研究。项目3假设SS大鼠中的一个突变(S)是导致该模型血管生成受损的原因。我们将：1)确定序列变异；2)证明这些变异在体外影响肾素调节；3)使用转基因方法，证明SS等位基因能够在体内消除正常的肾素调节和血管生成表型。这项PPG的合作研究将得到行政核心A、基因组和转基因核心B以及研究服务核心C的支持。

DESCRIPTION (provided by applicant): The goal of this PPG is to advance our understanding ofthe complex regulation and interplay of a set of genes residing in two different regions of chr 13 but which together are responsible, in large measure, for salt-induced hypertension, renal injury, and vascularity/angiogenesis of the microcirculation in the saltsensitive (SS) rat. The studies are collectively designed to explore how genetic polymorphisms are translated into integrated cellular, tissue, organ and whole animal function. Project 1 hypothesizes that sequence variants of one or more ofthe genes within a congenic region of chr 13 alter molecular regulatory networks affecting function of the medullary thick ascending limb (mTAL) of SS rats and contribute to the development of salt-sensitive hypertension and renal injury. This will tested by: 1) generating finished-level genomic sequence with complete annotation of this congenic region; 2) by constructing a molecular and physiological regulatory network of the mTAL epithelial cell and identifying pathways and genes that may contribute to hypertension and renal injury; and 3) by studying the impact of removing or overexpressing an important gene in the transcriptome/proteome/metabolome associated network. Project 2 will examine a novel hypothesis that non-protein-coding genes may play important roles in hypertension and related tissue injury. We hypothesize that miR-214 contributes to the development of salt-sensitive hypertension and renal injury and examine: 1) the functional contribution of the microRNA within the kidney; 2) examine downstream mechanisms mediating its effects, examine upstream trans and cis mechanisms; and 3) carry out a pilot study of miR-214 in human salt-sensitive hypertension and renal injury. Project 3 hypothesizes that a mutation(s) in the SS rat is responsible forthe impaired angiogenesis in this model. We will: 1) identify sequence variants; 2) demonstrate that these variants impact renin regulation in vitro; and 3) using a transgenic approach, demonstrate that the SS allele is capable of eliminating normal renin regulation and the angiogenic phenotype in vivo. The collaborative research of this PPG will be supported by Administrative Core A, Genomic and Transgenic Core B, and the Research Services Core C.