GENETIC DETERMINANTS OF SODIUM SENSITIVITY--CONGENIC MAPPING OF TWO LOCI

钠敏感性的遗传决定因素--两个位点的同源作图

• 批准号: 6110549
• 负责人: KLAUS LINDPAINTNER
• 金额: $ 24.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110549
• 关键词: artificial chromosomes; dietary sodium; disease /disorder model; disease /disorder proneness /risk; familial hypertension; gene mutation; genetic mapping; genetic markers; genetic polymorphism; genetic strain; kidney circulation; laboratory rat; molecular genetics; nucleic acid sequence; phenotype; polymerase chain reaction; single strand conformation polymorphism

Essential hypertension, like all complex diseases, is characterized by multifaceted interactions between genetic and environmental factors. Among environmental variables, dietary salt intake has long been recognized as a major modulator of blood pressure in some (sodium- sensitive) but not other (sodium-resistant) individuals. This spread of responses to an environmental influence is typical for ecogenetic interactions, where the phenotype effects of a given external perturbation differs according to the specific genetic make-up of the individual. Clinically, sodium-sensitivity plays an important role in the incidence of the disease as well as in the management of hypertensive patients, particularly among African-Americans. The study of sodium- dependent hypertensive mechanisms is therefore the focal point of the present SCOR application. The project at hand proposes to use a rat model of sodium-sensitive hypertension to identify and characterize genes that confer sodium-responsive modulation of blood pressure. We have previously crudely mapped two genes, BP-SP1 on chr. 10, and BP/DNa-1 on chromosome 6, that are involved in sodium-sensitivity in the spontaneously hypertensive, stroke prone rat. Using congenic experiments we have found that BP/SP-1 consists of two independent, but interacting loci, of which one, BP/SP-1b appears to be primarily involved in conferring sodium sensitivity. The specific aims of the presently proposed study are: (i) Development of a panel of targeted markers in the region of BP/SP- 1b and BP/DNa-1; (ii) Breeding of congenic lines carrying BP/SP-1b and BP/DNa-1, respectively, on WKY background. (iii) Precision phenotyping of these strains will allow pinpoint localization of the two genes and characterization of their specific phenotypic characteristics. (iv) Identification and characterization of the two genes will be pursued by positional cloning approaches.

原发性高血压与所有复杂疾病一样，其特点是 遗传和环境因素之间存在多方面的相互作用。 在环境变量中，膳食盐摄入量长期以来一直受到人们的关注。 被认为是某些人血压的主要调节剂（钠- 敏感）但不是其他（钠抗性）个体。这种传播 对环境影响的反应是生态遗传的典型反应 相互作用，其中给定外部的表型效应 扰动因特定基因组成而异 个人。临床上，钠敏感性在 该疾病的发病率以及高血压的治疗 患者，尤其是非裔美国人。钠的研究- 因此，依赖性高血压机制是研究的焦点。 介绍 SCOR 应用程序。手头的项目建议使用大鼠模型 钠敏感性高血压的识别和表征基因 赋予钠反应性血压调节。 我们之前粗略地绘制了两个基因，即 BP-SP1 基因。 10、和 6 号染色体上的 BP/DNA-1，参与钠敏感性 自发性高血压、中风易感大鼠。使用同类实验 我们发现BP/SP-1由两个独立但相互作用的 位点，其中一个 BP/SP-1b 似乎主要参与 赋予钠敏感性。目前的具体目标 拟议的研究是： (i) 开发 BP/SP 区域的一组靶向标记 1b 和 BP/DNA-1； (ii) 携带 BP/SP-1b 和 BP/DNA-1 的同系系的育种， 分别在WKY背景下。 (iii) 这些菌株的精确表型分析将允许精确定位 两个基因的定位及其特异性的表征 表型特征。 (iv) 两个基因的鉴定和表征 定位克隆方法所追求的。