SODIUM TRANSPORTER GENES AND ESSENTIAL HYPERTENSION

描述：(改编自《调查者摘要》)执着 高血压作为一种临床疾病的患病率和未根除的 尽管接受了治疗，但其靶器官并发症定义了临床任务 目的：探讨高血压的分子遗传学。阐明了 每种高血压亚型的潜在基因类型可能有助于 高血压病交互作用复杂性的机理分析 环境因素、遗传背景和基因交互作用，因此 为指导预防和干预提供关键工具 高血压的症状。认识到高血压的复杂性，和 综合多学科方法和合理的优先顺序方案 是必要的。这项建议主要针对盐敏感型高血压患者 与非裔美国人高血压相关的亚型，其中疾病是 以更高的患病率、发病率和死亡率为特征。机械论 分析需要研究一种战略性动物模型：Dahl 盐敏感(S)高血压和Dahl耐盐(R)正常血压大鼠 菌株。由于申请者已经确定了突变的Q276Lalphal Na，K-ATPase与突变的肾特异性布美他尼敏感性 达尔-S大鼠与达尔-R大鼠Na、K、Cl-共转运体的比较 假设α-Na，K-ATPase和/或 钠、钾、氯离子共转运体在盐敏感植物发育中的作用 达尔-S品系单独或单独或 以交互方式。确定优先顺序的具体目标是：i)确定 突变的α-Na，K-ATPase及其突变体的遗传贡献 钠、钾、氯转运蛋白基因与盐敏感型高血压表型的关系 DAHL S大鼠作为单基因、加性基因或乘性基因的高血压 阐明一个或两个定义的关键方面为 高血压基因；ii)确定突变的生物学后果 策略转基因S大鼠模型中α-Na，K-ATPase的表达 描述其在高血压中的机制作用；iii)确定 Dahl S和Dahl R的分子和功能特征 Na，K，Cl-共转运体变体，从而评估潜在的机制 Dahl盐敏感型大鼠高血压表型的生理作用。这个 成功完成本研究计划将定义a)字母 Na，K-ATPase作为真正的高血压基因；b) Na，K，Cl-共转运体作为候选高血压基因；c)将建立 未来高血压候选基因研究的基础 达尔S大鼠高血压模型的建立；以及d)将为直接 评估这些高血压基因在高血压发病中的作用 选择性人群中的高血压。

DESCRIPTION: (Adapted from the Investigator's Abstract) The persistent prevalence of hypertension as a clinical disease and the non- eradication of its target organ complications despite therapy defines the clinical mandate to investigate the molecular genetics of hypertension. The elucidation of underlying genotypes for each hypertension subtype could facilitate the mechanistic analysis of the complexities of hypertension due to interactive environmental factors, genetic background and gene interactions, thus providing a critical tool towards the directive prevention and intervention of hypertension. Cognizant of the complexities of hypertension, an integrated multidisciplinary approach with a rational prioritization scheme is necessary. This proposal focuses on the salt-sensitive hypertensive subtype relevant to hypertension in African Americans wherein the disease is characterized by greater prevalence, morbidity and mortality. Mechanistic analysis requires the investigation of a strategic animal model: the Dahl salt-sensitive (S) hypertensive and Dahl salt resistant (R) normotensive rat strains. Since the applicants have identified a mutant Q276Lalphal Na,K-ATPase and mutant renal-specific bumetanide-sensitive Na,K,Cl-cotransporter in Dahl S rats compared with Dahl R rats, they hypothesize that functional abnormalities in alpha1 Na,K-ATPase and/or Na,K,Cl- cotransporter contribute to the development of salt-sensitive hypertension and/or its renal complications in the Dahl S strain singly or interactively. The specific aims prioritized are: I) to determine the genetic contribution of the mutant alpha1 Na,K-ATPase and the mutant Na,K,Cl- cotransporter genes to the salt-sensitive hypertension phenotype of Dahl S rats as single, additive or multiplicative hypertension genes thus elucidating a critical aspect for the definition of one or both as hypertension genes; II) to determine the biologic consequences of the mutant alphal Na,K- ATPase in strategic transgenic Dahl S rat models in order to delineate its mechanistic role in hypertension; III) to determine the molecular and functional characteristics of Dahl S and Dahl R Na,K,Cl-cotransporter variants, thus assessing the potential mechanistic physiologic role in the Dahl salt-sensitive rat hypertensive phenotype. The successful completion of this research program will define a) the alphal Na,K-ATPase as bona fide hypertension gene; b) the status of the Na,K,Cl-cotransporter as a candidate hypertension gene; c) will establish the infrastructure for the study of future candidate hypertension genes in the Dahl S rat hypertensive model; and d) will pave the way for the direct assessment of the role of these hypertension genes in the development of hypertension in selective human populations.