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

与所有复杂疾病一样，原发性高血压的特点是 遗传因素和环境因素之间的多方面相互作用。 在环境变量中，食盐摄入量长期以来一直是 在某些情况下被认为是血压的主要调节剂(钠 敏感)，而不是其他(耐钠)个体。这一传播 对环境影响的反应是生态型的典型 相互作用，其中给定的外部环境的表型效应 扰动因基因组成的不同而不同。 个人的。临床上，钠敏感性在高血压病中起着重要作用。 疾病的发病率以及高血压的管理 患者，特别是非裔美国人。钠的研究-- 因此，依赖性高血压机制是高血压研究的重点 提出SCOR申请。手头的项目提议使用一种老鼠模型 以识别和表征钠敏感型高血压基因 对血压进行钠反应调节。 我们之前已经粗略地定位了两个基因，BP-SP1在CHR上。10，以及 位于6号染色体上的碱基/DNA-1，它们参与了小麦对钠的敏感性。 自发性高血压，容易中风的大鼠。利用同源基因实验 我们发现BP/SP-1由两个独立但又相互作用的分子组成 其中，BP/SP-1b似乎主要与 使人对钠敏感。当前的具体目标 建议的研究包括： (I)在BP/SP区域开发一组靶标-- 1b和BP/DNA-1； (2)携带BP/SP-1b和BP/DNA-1的同源品系的选育， 分别以WKY为背景。 (3)对这些菌株进行精确的表型鉴定将允许精确定位 这两个基因的定位及其特异性鉴定 表型特征。 (4)将对这两个基因进行鉴定和鉴定 通过位置克隆方法进行研究。

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.