CONGENIC STRAINS IN EXPERIMENTAL HYPERTENSION

实验性高血压中的同源菌株

• 批准号: 6462998
• 负责人: THEODORE W KURTZ
• 金额: $ 11.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6462998
• 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R IT（SHR）是研究最广泛的模型 基本高血压。但是，主要遗传因素负责 为了增加SHR的血压，仍有待鉴定。在 重组近交菌株以及F2和BackCross的连锁研究 源自SHR的种群，多个遗传标记 据报道，与血压升高（BP）的遗传有关。 在当前的研究中，我们将得出并表征 SHR的先天性菌株至：1）确定以下哪些链接反映 自发的完全表达所需的分子变体 高血压和2）使用菌株来绘制主要的血压调节 基因到狭窄的染色体区域。为了实现这些目标，我们将 创建多种shr的同类菌株。这些新菌株中的每一个都会 相对于单个染色体区域，与SHR祖细胞不同。 然后，我们将在一系列环境下测量这些菌株中的BP 状况。 SHR祖细胞菌株与BP的差异 先天性菌株将允许识别和隔离狭窄 染色体区域参与高血压的主要发病机理。 具体来说，我们将：1）使用反向交叉育种和基因组选择 用SHR中选择选定的染色体段的技术 来自正常棕道（BN）的相应染色体片段 鼠。以这种方式，将至少有10种同类菌株的小组 创建每个应变与SHR祖细胞仅在A中不同的创建 单染色体区域。 2）确定哪个转移的染色体 段包含与高血压相关的基因，通过比较 SHR祖细胞菌株BP的先天性菌株。 radiotelemetry 换能器将用于连续测量心率和主动脉 在不同的发展阶段和不同的压力下 环境状况（正常饮食NACL；高饮食NACL：高 压力（约束）。高NaCl结合高应力）。 3）映射成本 有效的BP调节基因以更受限制的染色体区域 测量具有不同的重组先天性菌株的BPS 染色体感兴趣的区域的重叠部分。我们也会 通过测量血压来测试这些基因的相互作用效应 在通过选定的杂种杂交得出的杂种线中 菌株。调节心脏质量的QTL将以类似的方式绘制。 因此，新的同种菌株将使我们能够明确测试 关于特定染色体区域在 自发性高血压的发病机理并为所需的基础奠定了基础 对于最终的分子变体的位置克隆 血压升高。