NEW EXPERIMENTAL MODELS OF HYPERTENSION

描述(申请人提供)：自发性高血压大鼠 自发性高血压(SHR)是目前研究最广泛的高血压动物模型。 是研究血液药理学和生理学的宝贵工具 压力控制。然而，尽管对这种模型进行了30年的研究，但 导致自发性高血压的主要机制尚不清楚。 最近，我们成功地捕捉到了一个数量性状基因座(QTL) 独一无二的同源基因8号染色体狭窄片段内的高血压 SHR菌株。在目前的研究中，我们将利用这种同源菌株。 以及成熟的全基因组表达分析和减数分裂策略 作图以确定对此影响负责的分子病变(S) 8号染色体区域对血压的影响。我们将寻求两种选择 使用互补策略的假设如下：假设1.a 高血压基因存在于8号染色体的目标片段中，即 SHR和SHR同源株之间的差异表达 疑似参与本病原发病的主要器官 自发性高血压(脑、肾上腺或肾脏)。因此，我们 将在目标染色体内寻找高血压的候选者 通过筛选这些基因之间的差异表达来分段 SHR和SHR同源株的器官，并映射回 8号染色体的同源片段。假设2.存在高血压基因 在8号染色体的目标片段中，没有差异表达 SHR和SHR同源株之间的差异。为这个替代方案做掩护 可能，我们还将通过以下方式缩小高血压基因的位置 自交系F2分离群体的减数分裂图谱分析 前体菌株和携带靶基因区域的SHR同源菌株 来自BN株的8号染色体。高血压候选基因将会是 用cDNA筛选技术分离鉴定表达于 位于该染色体区域内的大脑、肾上腺或肾脏。

DESCRIPTION (provided by the applicant): The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension and has been a valuable tool for studying the pharmacology and physiology of blood pressure control. However, despite 30 years of research with this model, the primary mechanisms responsible for hypertension in the SHR remain undefined. Recently, we have succeeded in trapping a quantitative trait locus (QTL) for hypertension within a narrow segment of chromosome 8 in a unique congenic strain of SHR. In the current studies, we will exploit this congenic strain together with proven strategies of genome wide expression analysis and meiotic mapping to identify the molecular lesion(s) responsible for the effect of this region of chromosome 8 on blood pressure. We will pursue two alternative hypotheses using complementary strategies as follows: Hypothesis 1. A hypertension gene exists within the target segment of chromosome 8 that is differentially expressed between the SHR and the SHR congenic strain in one of the major organs suspected to be involved in the primary pathogenesis of spontaneous hypertension (brain, adrenal gland, or kidney). Accordingly, we will search for candidates for hypertension within the target chromosome segment by screening for genes that are differentially expressed between these organs of the SHR and the SHR congenic strain and that map back within the congenic segment of chromosome 8. Hypothesis 2. A hypertension gene exists within the target segment of chromosome 8 that is not differentially expressed between the SHR and the SHR congenic strain. To cover for this alternative possibility, we will also narrow the location of the hypertension gene by meiotic mapping analysis of a segregating F2 population derived from the SHR progenitor strain and the SHR congenic strain that carries the target region of chromosome 8 from the BN strain. Hypertension candidate genes will then be isolated using cDNA screening techniques to identify genes expressed in the brain, adrenal gland, or kidney that map within this chromosome region.