CONGENIC STRAINS IN EXPERIMENTAL HYPERTENSION

实验性高血压中的同源菌株

• 批准号: 6327713
• 负责人: THEODORE W KURTZ
• 金额: $ 25.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327713
• 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.

自发性高血压患者它（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血压升高的原因尚待确定。在 重组近交系和F2及回交中的连锁研究 在来自SHR的群体中，多个遗传标记已被用于 据报道与血压升高（BP）的遗传有关。 在目前的研究中，我们将推导和表征一个库， SHR的同源株，以：1）确定这些联系中的哪一个反映了 完全表达自发的 高血压和2）使用菌株映射主要血压调节 缩小染色体区域的基因。为了实现这些目标，我们将 创造了多种SHR的同类品系。这些新菌株中的每一种都会 与SHR祖先的区别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BP。 条件自发性高血压大鼠（SHR）祖细胞株与 同类菌株将允许鉴定和分离狭窄的 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 技术来取代选定的染色体片段在SHR与 来自血压正常的布朗-挪威（BN）的相应染色体片段 大鼠以这种方式，一组至少10个同源菌株将被检测到。 其中每个菌株与SHR祖先的差异仅在于 单染色体区2)确定哪条转移的染色体 片段包含与高血压相关的基因，通过比较 与SHR祖株的BP同源的菌株。无线电遥测术 传感器将用于连续测量心率和主动脉瓣 在不同的发展阶段和不同的压力下， 环境条件（正常饮食NaCl;高饮食NaCl：高 压力（约束）。高NaCl结合高胁迫）。3)映射成本 BP调节基因，以更有限的染色体区域， 测量携带不同的细菌的重组同源菌株中的BP 目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 在通过选择的同类基因的杂交育种得到的杂交系中， 菌株调节心脏质量的QTL将以类似的方式作图。 因此，新的同类菌株将使我们能够明确地测试 关于特定染色体区域在细胞中作用的假说 自发性高血压的发病机制，并奠定了基础 用于最终定位克隆负责 血压升高