Role of Na+ Transporter Genes in Essential Hypertension

描述(由申请人提供)：尽管有重要的 高血压的遗传学基础研究进展，大量工作 仍需在持续临床工作的累积背景下完成 委托书。从本质上讲，高血压仍然是一种高度流行的疾病。 它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。中风和肾脏疾病。 很明显，(1)基因的相互作用必须考虑到遗传因素。 分析复杂的遗传性疾病(例如，高血压)； (2)良好对照动物模型实验中的基因互作分析 再加上对基因分离的人类进行优先顺序的后续测试 种群提供了一种强有力的实验策略。这些认识伴随着 具有洞察力、观察力以及实验性方法验证 在之前的研究方案中获得的，为我们提供了临床和 科学授权研究以下假设：单向 A1-Na，K-ATPase(A1NK)与Na，K，2c1-共转运蛋白(NKC)的基因相互作用 应用核糖核酸技术鉴定达尔-S大鼠高血压易感性基因 交联性分析反映了体内分子间的相互依赖 这些转运体因此应该可以通过体内测试 战略性转基因实验。因此，以下是具体目标 这项持续研究提案的优先事项：目标I：确定体内 肾脏特异性遗传相关性的生物学意义 Na，K，2Cl-共转运蛋白基因与Dahl-S大鼠高血压的关系目标二：确定 统计相互关联的活体生物学意义 A1NK和NKC基因在盐敏感型高血压发病中的双重作用 转基因(双基因)Tg[Ra 1NKx Nkc-F]和Tg[Ra 1NKx Nkc-A]Dahl S大鼠。 这项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-共转运蛋白 DAHL S大鼠的高血压易感基因；和b)将为 直接评估这些基因在高血压易感性中的作用 在不同的人类群体中。

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.