Biochemistry and Genetics of Hypertension

描述（由申请人提供）：本提案的总体目标是确定控制血压的基因，即血压数量性状位点（QTL）。以达尔盐敏感(S)大鼠为动物模型。目前，研究中的大多数血压QTL已经通过同源菌株在连锁图谱上定位，其中（供体）菌株含有QTL的染色体片段通过选择性育种模式渗入（受体）S菌株。这种携带替换的低血压QTL等位基因的同源菌株比S大鼠血压低。在本研究中，通过替换作图，将大鼠第5、9和10号染色体上含有同源片段的QTL减少到染色体间隔小于1厘米。替代作图包括系统地减少基因渗入染色体片段的大小。一系列含有逐渐缩短重叠供体染色体片段的同源亚株被构建。确定哪些菌株显示或不显示与S大鼠不同的血压，从而确定哪些菌株包含或不包含取代的QTL等位基因。从这个信息可以推断出含有染色体区域的QTL，通常小于1厘米。在这段时间内，候选基因将被评估供体和受体菌株(S)之间的DNA序列变异和表达差异。由此可以预期一个强有力的候选基因，从逻辑上讲，它就是导致血压升高的基因。因此，在大鼠中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.