Genetics of the Sodium-Lithium Countertransport

描述（由申请人提供）：寻找引起原发性高血压的基因已经进行了近二十年，但这些基因的作用及其基因组位置的鉴定仍然难以捉摸。 原发性高血压易感基因的发现进展缓慢，这是由于原发性高血压的多基因性质以及衰老和遗传-环境相互作用对这种疾病表型表达的混淆作用。 近年来的研究表明，活性氧（ROS），这是在衰老过程中的决定因素，也是原发性高血压的发展和表达的主要因素。 这些表型之一是钠锂反向转运（SLC）。 如在EB病毒（EBV）永生化淋巴母细胞中表达的，SLC与携带编码在谷胱甘肽代谢中起关键作用的酶的基因簇的基因座遗传相关和连接。 鉴于谷胱甘肽是细胞防御ROS的中心，这些遗传关联/连锁发现与以下观察结果一致：a）来自高血压供体的EBV永生化淋巴母细胞显示ROS产生增加，B）来自高血压受试者的红细胞显示低谷胱甘肽水平和氧化/还原型谷胱甘肽比率增加，c）硫醇代谢改变SLC的活性，和d）永生化淋巴母细胞中还原型谷胱甘肽水平增强SLC活性。 本项目的目标如下：1. 测量来自53个犹他州家庭（包括561个个体）的EBV永生化淋巴母细胞中的SLC活性; 2. 使用候选基因和基因组扫描方法进行遗传分析，以阐明导致SLC活性变化的基因; 3. 研究EBV永生化淋巴母细胞中SLC活性与供体心血管指标的关系; 探讨永生化淋巴母细胞氧化还原状态与SLC的关系。 这将通过操纵永生化淋巴母细胞中的ROS和谷胱甘肽水平来完成。 研究结果将增强我们对心血管疾病（包括原发性高血压）遗传决定因素的理解，并提供一个机制的观点，将原发性高血压的病理生理学与ROS的生物学联系起来。

DESCRIPTION (provided by applicant): The search for genes causing essential hypertension has been ongoing for almost two decades, yet the identification of the effect of these genes and their genomic location has remained elusive. The slow progress in finding genes that harbour susceptibility to essential hypertension has been attributed to the polygenic nature of essential hypertension and the confounding effects of aging and genetic - environmental interactions on the phenotypic expressions of this disorder. Recent studies have indicated that reactive oxygen species (ROS), which are determinants in the aging process, are also major factors in the development and expression of essential hypertension. One of these phenotypes is the sodium lithium countertransport (SLC). As expressed in Epstein-Barr virus (EBV) immortalized lymphoblasts, the SLC is genetically associated and linked with loci harboring clusters of genes encoding enzymes that play key roles in glutathione metabolism. Given that glutathione is at the center of the cellular defense against ROS, these genetic association/linkage findings are in line with the observations that: a) EBV immortalized lymphoblasts from hypertensive donors show an increase in ROS production, b) erythrocytes from hypertensive subjects show low glutathione level and an increase in the oxidized/reduced glutathione ratio, c) thiol metabolism modifies the activity of the SLC, and d) reduced glutathione levels in immortalized lymphoblasts enhances SLC activity. The objectives of this project are as follows: 1. Measure SLC activity in EBV immortalized lymphoblasts from 53 Utah families comprising 561 individuals; 2. Perform genetic analysis using candidate genes and genome-scan approaches to elucidate genes that account for variations in SLC activity; 3. Examine the relationship between SLC activity in EBV immortalized lymphoblasts and cardiovascular indices in the donors; and 4. Explore the mechanisms that link the redox status of immortalized lymphoblasts with the SLC. This will be done by manipulating ROS and glutathione levels in the immortalized lymphoblasts. Results will enhance our understanding of genetic determinants of cardiovascular diseases, including essential hypertension, and provide a mechanistic perspective that links the pathophysiology of essential hypertension to the biology of ROS.