CONGENIC STRAINS IN EXPERIMENTAL HYPERTENSION

实验性高血压中的同源菌株

• 批准号: 6272746
• 负责人: THEODORE W KURTZ
• 金额: $ 26.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272746
• 关键词: animal breeding; animal population genetics; dietary sodium; environmental stressor; familial hypertension; gene environment interaction; genetic mapping; genetic markers; genetic polymorphism; genetic regulation; genetic strain; heart rate; laboratory rat; nutrition related tag; polymerase chain reaction; quantitative trait loci; spontaneous hypertensive rat; telemetry

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.

自发性高血压（SHR）是研究最广泛的模型 原发性高血压。然而，主要的遗传因素 SHR 血压升高的原因仍有待确定。在 重组自交系以及 F2 和回交中的连锁研究 从 SHR 衍生的种群中，多个遗传标记已被 据报道与血压升高（BP）的遗传有关。 在当前的研究中，我们将推导并描述一个库 SHR 的同源菌株：1) 确定这些联系中的哪一个反映了 自发性完全表达所必需的分子变异 高血压和 2) 使用菌株来绘制主要血压调节图 缩小染色体区域的基因。为了实现这些目标，我们将 创造多个同系 SHR 品系。这些新菌株中的每一个都将 与 SHR 祖细胞的不同之处在于单个染色体区域。 然后我们将在一系列环境条件下测量这些菌株的血压 状况。 SHR 祖株和 SHR 祖株之间的血压差异 同源菌株将允许鉴定和分离狭窄的菌株 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）使用回交育种和基因组选择 技术来替换 SHR 中选定的染色体片段 来自正常血压 Brown-Norway (BN) 的相应染色体片段 鼠。以这种方式，一组至少 10 个同源菌株将被 所创建的每个菌株与 SHR 祖细胞仅在一个方面有所不同 单染色体区域。 2) 确定转移的是哪条染色体 通过比较各片段的血压，包含与高血压相关的基因 同类菌株与 SHR 祖菌株的 BP 的关系。无线电遥测 传感器将用于连续测量心率和主动脉 不同发展阶段、不同时期面临的压力 环境条件（正常膳食氯化钠；高膳食氯化钠：高 压力（约束）。高氯化钠与高应力相结合）。 3）绘制成本图 通过将有效的 BP 调节基因作用于更受限制的染色体区域 测量携带不同基因的重组同源菌株中的 BP 感兴趣的染色体区域的重叠片段。我们还将 通过测量血压来测试这些基因的相互作用效应 在通过选定的同类品种杂交而衍生的杂交品系中 菌株。调节心脏质量的 QTL 将以类似的方式进行定位。 因此，新的同源菌株将使我们能够明确地测试 关于特定染色体区域的作用的假设 自发性高血压的发病机制及所需奠定基础 用于最终定位克隆负责的分子变体 血压升高。