SODIUM TRANSPORTER GENES AND ESSENTIAL HYPERTENSION

描述：（改编自研究者摘要） 高血压作为一种临床疾病的流行率以及 其靶器官并发症尽管治疗定义了临床任务 研究高血压的分子遗传学。 阐明 每种高血压亚型的潜在基因型可能有助于 高血压复杂性的机制分析，由于交互作用， 环境因素、遗传背景和基因相互作用， 为直接预防和干预提供重要工具 高血压 认识到高血压的复杂性， 综合性多学科方法，合理安排优先次序 是必要的. 该建议的重点是盐敏感性高血压 与非裔美国人的高血压相关的亚型，其中所述疾病是 其特点是发病率、发病率和死亡率较高。 机械论 分析需要研究一个战略性的动物模型：达尔 盐敏感性高血压和Dahl盐抵抗性正常血压大鼠 菌株 由于申请人已经鉴定了突变体Q276 Leptidal Na，K-ATPase和突变型肾特异性布美他尼敏感性 与Dahl R大鼠相比，Dahl S大鼠的Na，K，Cl-协同转运蛋白 假设α 1 Na，K-ATP酶和/或 Na，K，Cl-协同转运蛋白参与盐敏感性的形成 高血压和/或其肾脏并发症在Dahl S株单独或 交互式。 优先考虑的具体目标是：（一）确定 突变体α 1 Na，K-ATP酶和突变体α 1 Na，K-ATP酶的遗传贡献 Na，K，Cl-协同转运蛋白基因与盐敏感性高血压表型的关系 Dahl S大鼠作为单一的，加性或倍增的高血压基因， 阐明了一个或两个定义的关键方面， 高血压基因; II）确定突变的生物学后果 在策略性转基因Dahl S大鼠模型中， 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-协同转运蛋白变体，从而评估潜在的机制 Dahl盐敏感大鼠高血压表型的生理作用。 的 本研究计划的成功完成将定义a） Na，K-ATP酶是真正的高血压基因; B）高血压基因的状态， Na，K，Cl-协同转运蛋白作为候选高血压基因; c）将建立 研究未来高血压候选基因的基础设施， Dahl S大鼠高血压模型;和d）将为直接 评估这些高血压基因在发展中的作用， 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.