Genetics of the Sodium-Lithium Countertransport

描述(申请人提供)：对导致高血压的基因的研究已经进行了近20年，然而这些基因的作用和它们的基因组位置的鉴定仍然难以捉摸。高血压易感基因的发现进展缓慢，归因于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杂影响。最近的研究表明，作为衰老过程中的决定因素的活性氧物种(ROS)也是原发性高血压发生和表达的主要因素。钠锂逆向转运(SLC)是这些表型之一。正如在EB病毒(EBV)永生化的淋巴母细胞中表达的那样，SLC与含有编码酶的基因簇的基因座存在遗传关联，这些基因在谷胱甘肽代谢中发挥关键作用。鉴于谷胱甘肽是抵抗ROS的细胞防御的中心，这些遗传关联/连锁发现与以下观察结果一致：a)来自高血压捐赠者的EBV永生化淋巴母细胞显示ROS产生增加，b)高血压患者的红细胞显示低水平的谷胱甘肽和氧化/还原的谷胱甘肽比率增加，c)硫醇代谢改变SLC的活性，以及d)永生化淋巴母细胞中降低的谷胱甘肽水平增强SLC活性。该项目的目标如下：1.测量来自犹他州53个家庭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.检查EBV永生化淋巴母细胞中SLC活性与捐赠者心血管指数的关系；以及4.探索永生化淋巴母细胞的氧化还原状态与SLC之间的联系机制。这将通过操纵永生化淋巴母细胞中的ROS和谷胱甘肽水平来实现。研究结果将加深我们对包括高血压在内的心血管疾病的遗传决定因素的理解，并提供一个将高血压的病理生理学与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.