CONGENIC STRAINS IN EXPERIMENTAL HYPERTENSION

自发性高血压RIT(SHR)是研究最广泛的动物模型 高血压病。然而，主要的遗传因素导致了 自发性高血压患者血压升高的原因仍有待确定。在……里面 重组自交系及F2代与回交的连锁研究 源于自发性高血压病的群体，多个遗传标记已被 据报道，这与遗传导致的血压升高有关。 在目前的研究中，我们将派生和描述一个库 SHR的同源菌株：1)确定这些联系中的哪些反映 自发性基因充分表达所需的分子变体 高血压和2)使用这些菌株来定位主要的血压调节 缩小染色体区域的基因。为了实现这些目标，我们将 创造多个SHR的同源株。这些新菌株中的每一个都将 在单个染色体区域上不同于SHR祖细胞。 然后，我们将在一系列环境条件下测量这些菌株的BP 条件。自发性高血压祖系与自发性高血压大鼠血压的差异 同源菌株将可用于鉴定和分离窄带病毒 染色体区域参与高血压的主要发病机制。 具体来说，我们将：1)利用回交育种和基因组选择 将自发性高血压病中选定的染色体片段替换为 正常血压的布朗-挪威(BN)的相应染色体片段 老鼠。以这种方式，由至少10个同源菌株组成的小组将 其中每个品系与SHR祖代的不同之处仅在于 单染色体区域。2)确定转移的染色体中的哪一个 片段包含与高血压相关的基因，通过比较 同源株与SHR祖株的BP同源。无线电遥测 传感器将被用来连续测量心率和主动脉 不同发展阶段和不同情况下的压力 环境条件(正常膳食氯化钠；高膳食氯化钠：高 压力(约束)。高盐与高胁迫相结合)。3)绘制成本地图 通过以下方式对更受限制的染色体区域进行有效的BP调节基因 在携带不同基因的重组同源菌株中测量BP 感兴趣的染色体区域的重叠片段。我们还将 通过测量血压来检验这些基因的交互作用 用选育的同源基因杂交获得的杂交系 菌株。调节心脏质量的QTL将以类似的方式绘制出来。 因此，新的同源毒株将使我们能够明确地检测 关于特定染色体区域在体内的作用的假说 为自发性高血压的发病机制奠定必要的基础 为最终定位克隆负责的分子变异 血压升高。

The spontaneously hypertensive rit (SHR) is the most widely studied model of essential hypertension. however the primary genetic factors responsible for increased blood pressure in the SHR remain to be identified. In linkage studies in recombinant inbred strains and in F2 and backcross populations derived from the SHR, multiple genetic markers have been reported to be linked to the inheritance of increased blood pressure (BP). In the current studies, we will derive and characterize a library of congenic strains of SHR to: 1) determine which of these linkages reflect molecular variants necessary for full expression of spontaneous hypertension and 2) use the strains to map major blood pressure regulatory genes to narrow chromosome regions. To accomplish these goals, we will create multiple congenic strains of SHR. Each of these new strains will differ from the SHR progenitor with respect to a single chromosome region. We will then measure BP in these strains under a range of environmental conditions. Differences in BP between the SHR progenitor strain and the congenic strains will allow for the identification and isolation of narrow chromosome regions involved in the primary pathogenesis of hypertension. Specifically, we will: 1) Use backcross breeding and genomic selection techniques to replace selected chromosome segments in the SHR with corresponding chromosome segments from the normotensive Brown-Norway (BN) rat. In this fashion, a panel of at least 10 congenic strains will be created in which each strain differs from the SHR progenitor in only a single chromosome region. 2) Determine which of the transferred chromosome segments contain genes relevant to hypertension by comparing the BP of the congenic strains to the BP of the SHR progenitor strain. Radiotelemetry transducers will be used to continuously measure heart rate and aortic pressures during different stages of development and under different environmental conditions (normal dietary NaCl; high dietary NaCl: high stress (restraint). high NaCl combined with high stress). 3) Map the cost potent BP regulatory genes to more restricted chromosome regions by measuring BPs in recombinant congenic strains that carry different overlapping segments of the chromosome regions of interest. We will also test for interaction effects of these genes by measuring blood pressures in hybrid lines derived by the cross-breeding of selected congenic strains. QTLs regulating cardiac mass will be mapped in a similar fashion. Thus, the new congenic strains will enable us to definitively test hypotheses about the role of specific chromosome regions in the pathogenesis of spontaneous hypertension and lay the groundwork required for the eventual positional cloning of molecular variants responsible for the increased blood pressure.