Genetics of the Sodium-Lithium Countertransport

描述（由申请人提供）：对原发性高血压基因的研究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。发现原发性高血压易感性基因的缓慢进展归因于原发性高血压的多基因性质，以及衰老和遗传-环境相互作用对该病表型表达的混淆作用。最近的研究表明，活性氧（ROS）是衰老过程中的决定因素，也是原发性高血压发生和表达的主要因素。其中一种表型是钠锂反转运（SLC）。在eb病毒（EBV）永生化淋巴母细胞中表达的SLC与基因座相关，并与编码谷胱甘肽代谢中起关键作用的酶的基因簇相关。鉴于谷胱甘肽是细胞防御ROS的核心，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/还原性谷胱甘肽比例的增加，c)硫醇代谢改变了SLC的活性，d)永生化淋巴细胞中谷胱甘肽水平的降低增强了SLC活性。本项目的目标如下：1。测定53个犹他州EBV永活淋巴母细胞SLC活性，包括561个个体；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. 探讨EBV永活淋巴细胞SLC活性与供体心血管指标的关系；和4。探索永生化淋巴细胞氧化还原状态与SLC之间的联系机制。这将通过操纵永生淋巴母细胞中的ROS和谷胱甘肽水平来实现。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，并提供将原发性高血压的病理生理与ROS生物学联系起来的机制视角。

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.