Role of Na+ Transporter Genes in Essential Hypertension

描述（由申请人提供）：虽然有重大 在高血压遗传基础的研究方面取得了进展， 仍有待于在持续的临床 授权。实质上，原发性高血压仍然是一种高度流行的疾病 并且仍然是美国主要死亡原因的主要风险因素： 冠状动脉疾病心力衰竭心律失常中风和肾病。 很明显，（1）基因相互作用必须考虑到遗传因素， 复杂遗传疾病的分析，（例如，原发性高血压）;以及 (2)良好对照动物模型实验中的基因相互作用分析 再加上在遗传隔离的人类中优先进行的后续测试， 人口提供了一个强大的实验策略。这些认识沿着 通过洞察力、观察以及实验方法验证， 在以前的研究方案中获得的，为我们提供了临床和 科学授权调查以下假设： α 1 Na，K-ATP酶（α 1 NK）和Na，K，2C 1-协同转运蛋白（NKC）的基因相互作用 Dahl S大鼠中增加高血压易感性的基因 相互交联分析反映了在体内的分子相互依赖性， 这些转运蛋白，因此它应该适合于体内测试， 战略性转基因实验因此，以下具体目标是 优先考虑这项持续的研究提案：目的I：确定体内 肾特异性抗体基因相关性的生物学意义 Na，K，2Cl协同转运体基因与Dahl S大鼠高血压的关系目标二：确定 统计交互相关的体内生物学意义 盐敏感性高血压患者a1 NK和NKC基因的表达 转基因（双基因）Tg[Ra 1 NK x nkc-F）]和Tg[Ra 1 NK x nkc-A）] Dahl S大鼠。 本研究计划的成功完成将定义a） alNa，K-ATPase和布美他尼敏感的Na，K，2Cl-协同转运蛋白作为真正的 Dahl S大鼠中的高血压易感基因;和B）将为 直接评估这些基因在高血压易感性中的作用 在不同的人群中。

DESCRIPTION (provided by applicant): Although there has been significant progress in the investigation of the genetic basis of hypertension, much work remains to be done against the cumulative backdrop of persistent clinical mandates. In essence, essential hypertension remains a highly prevalent disease and remains a major risk factor for the top causes of mortality in the USA: coronary artery disease, heart failure, arrhythmias. stroke and renal disease. It has become clear that (1) gene interaction must be factored into the genetic analysis of complex genetic diseases, (e.g., essential hypertension); and that (2) gene interaction analysis in well-controlled animal model experiments coupled to prioritized subsequent testing in genetically isolated human populations provides a robust experimental strategy. These realizations along with insights, observations, as well as experimental approach validation obtained in the previous research proposal, provide us with the clinical and scientific mandates to investigate the following hypothesis: The unidirectional gene interaction of a1 Na,K-ATPase (a1NK) and Na,K,2C1-cotransporter (NKC) genes increasing susceptibility to hypertension identified in Dahl S rats by an intercross linkage analysis reflects an in vivo molecular interdependence of these transporters and as such it should be amenable to in vivo testing via strategic transgenic experiments. Accordingly, the following specific aims are prioritized for this continuing research proposal: Aim I: Determine the in vivo biological significance of the genetic correlation of the renal-specific Na,K,2Cl-cotransporter gene with hypertension in Dahl S rats. Aim II: Determine the in vivo biological significance of the statistical interactive correlation of a1NK and NKC genes on salt-sensitive hypertension by developing dual transgenic (bigenic) Tg[Ra 1NK x nkc-F)] and Tg[Ra 1NK x nkc-A)] Dahl S rats. The successful completion of this research program will define a) the alNa,K-ATPase and the bumetanide-sensitive Na,K,2Cl-cotransporter as bona fide hypertension susceptibility genes in Dahl S rats; and b) will pave the way for the direct assessment of the role of these genes in hypertension susceptibility in different human populations.