Genetics of the Sodium-Lithium Countertransport

钠-锂逆向转运的遗传学

• 批准号: 6881158
• 负责人: ABRAHAM AVIV
• 金额: $ 57.81万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881158
• 关键词: Epstein Barr virus; aging; cell line; clinical research; essential hypertension; family genetics; free radical oxygen; gene environment interaction; gene expression; gene mutation; genetic screening; genetic susceptibility; glutathione; human genetic material tag; ion transport; linkage mapping; lithium; lymphoblast; nucleic acid amplification techniques; pathologic process; polymerase chain reaction; single nucleotide polymorphism; sodium; statistics /biometry

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.

描述（由申请人提供）：对引起原发性高血压的基因的研究已经持续了近二十年，但这些基因的作用及其基因组位置的鉴定仍然难以捉摸。 寻找原发性高血压易感基因的进展缓慢，归因于原发性高血压的多基因性质以及衰老和遗传-环境相互作用对该疾病表型表达的混杂影响。 最近的研究表明，活性氧（ROS）是衰老过程的决定因素，也是原发性高血压发生和表现的主要因素。 这些表型之一是钠锂逆向转运（SLC）。 正如 Epstein-Barr 病毒 (EBV) 永生化淋巴母细胞中所表达的那样，SLC 在遗传上与含有编码在谷胱甘肽代谢中发挥关键作用的酶的基因簇的基因座相关。 鉴于谷胱甘肽是针对 ROS 的细胞防御的核心，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，d) 永生化淋巴母细胞中谷胱甘肽水平的降低增强了 SLC 的活性。 该项目的目标如下： 1. 测量来自 53 个犹他州家庭（包括 561 名个体）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. 检测供体EBV永生化淋巴母细胞SLC活性与心血管指标的关系； 4.探索永生化淋巴母细胞的氧化还原状态与SLC的联系机制。 这将通过操纵永生化淋巴母细胞中的 ROS 和谷胱甘肽水平来完成。 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学与 ROS 生物学联系起来的机制视角。