NEW EXPERIMENTAL MODELS OF HYPERTENSION

性状（由申请方提供）：自发性高血压大鼠 (SHR)是研究最广泛的原发性高血压动物模型， 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30年的研究与此模型， 在SHR中引起高血压的主要机制仍不清楚。 最近，我们成功地捕获了一个数量性状位点（QTL）， 高血压发生在8号染色体狭窄片段内， SHR品系。在目前的研究中，我们将利用这一同源菌株 连同已被证明的全基因组表达分析和减数分裂的策略 映射以识别负责这种效应的分子病变 8号染色体上的区域对血压的影响。我们将寻求两种选择 假设使用补充策略如下：假设1。一 高血压基因存在于8号染色体的靶片段内， 在SHR和SHR同源株之间的差异表达， 怀疑参与原发性发病机制的主要器官 自发性高血压（脑、肾上腺或肾）。因此我们 将在目标染色体中寻找高血压的候选者 通过筛选这些基因之间差异表达的基因来进行分段， SHR和SHR同类品系的器官，并映射回 8号染色体的同源片段。假设2.高血压基因存在 在8号染色体的靶片段内， SHR和SHR同源株之间的差异为了掩护这个替代方案 可能性，我们还将缩小高血压基因的位置， SHR分离F_2群体的减数分裂作图分析 祖菌株和携带靶区域的SHR同源菌株 BN菌株的8号染色体。高血压候选基因将被 使用cDNA筛选技术分离，以鉴定在 大脑、肾上腺或肾脏的染色体区域。

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.