Biochemistry and Genetics of Hypertension

描述(申请人提供)：这项建议的总体目标是确定控制血压的基因，即血压数量性状基因座(QTL)。以达尔盐敏感(S)大鼠为动物模型。在这一点上，大多数研究中的血压QTL已经被定位在连锁图谱上，利用同源品系，其中包含QTL的染色体片段来自(供体)品系，通过选择育种范式导入(受体)S品系。这种携带替代低血压QTL等位基因的同源品系比S大鼠的血压更低。在这一建议中，包含大鼠第5、9和10号染色体上的同源片段的QTL将通过替换作图减少到小于1 centiMorgan的染色体间隔。替代作图包括系统地减小导入的同源染色体片段的大小。构建了一系列含有逐渐变短的重叠供体染色体片段的同源亚株。确定哪些品系显示或不显示与S大鼠不同的血压，从而确定哪些品系包含或不包含替换的QTL等位基因。根据这些信息，可以推断出包含染色体区域的QTL，该区域通常小于1 centiMorgan。在这个区间内的候选基因将被评估供体和受体(S)毒株之间的dna序列变异和表达差异。由此可以预料到一个强有力的候选基因，从逻辑上讲，它是导致血压的基因。在大鼠体内发现的血压基因为理解血压控制的生理/生化途径提供了新的候选基因。这些基因很可能为人类高血压的治疗干预提供靶点。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to identify the genes controlling blood pressure, that is, the blood pressure quantitative trait loci (QTL). The Dahl salt sensitive (S) rat is used as an animal model. At this point, most of the blood pressure QTL under study have been localized on linkage maps by the use of congenic strains in which a QTL-containing chromosomal segment from a (donor) strain is introgressed by a selective breeding paradigm into the (recipient) S strain. Such a congenic strain carrying a substituted low blood pressure QTL allele has a lower blood pressure than S rats. In this proposal, the QTL containing congenic segments on rat chromosomes 5, 9 and 10 will be reduced to chromosomal intervals of less than 1 centiMorgan by substitution mapping. Substitution mapping consists of systematically reducing the size of the introgressed congenic chromosomal segment. A series of congenic substrains containing progressively shorter overlapping donor chromosomal segments is constructed. It is determined which strains do, or do not, show a blood pressure different from S rats, and thus which strains do, or do not, contain the substituted QTL allele. From this information one can deduce the QTL containing chromosomal region which will generally be less than 1 centiMorgan. Candidate genes in this interval will be evaluated for DNA sequence variation and expression differences between the donor and recipient (S) strain. From this a strong candidate gene can be expected, which is logically the causative blood pressure gene. Blood pressure genes thus identified in the rat provide new candidate genes for understanding physiological/biochemical pathways of blood pressure control. Such genes are likely to provide targets for therapeutic intervention in human hypertension.