MODELS FOR STUDYING THE GENETICS OF HYPERTENSION

研究高血压遗传学的模型

• 批准号: 6183479
• 负责人: OLIVER SMITHIES
• 金额: $ 58.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183479
• 关键词: angiotensin II; atrial natriuretic peptide; blood volume; disease /disorder model; essential hypertension; gene dosage; gene expression; gene targeting; genetic recombination; genetic regulation; genetically modified animals; histochemistry /cytochemistry; homeostasis; laboratory mouse; model design /development; phenotype; polymerase chain reaction; radioimmunoassay; renin

The objective of this renewal application is to continue work begun during the prior funding period focused on the analysis of the role of various candidate genes in hypertension through the manipulation of their dosage in genetically engineered mice. This prior work involved using gene targeting to create mice with zero, one, two, three, and four copies of candidate genes targeted at their normal chromosomal locations and then assessing the impact of these defined alterations on hypertension in the mouse. The studies demonstrated that gene dosage determines the levels of expression of these genes which either directly impacted on blood pressure, or had blunted effects on blood pressure due to homeostatic adjustments mediated by other genetic elements. The hypothesis that was developed from these prior studies and which is to be tested in the proposed studies are that variations in the level of expression of a variety of genes will lead to blood pressure changes that may be a reflection of increased expression of the manipulated genes or may be blunted or completely missed depending on the homeostatic adjustments mediated by other elements. Dr. Smithies interprets these blunted changes as virtual blood pressure changes since homeostatic adjustments (i.e.) altered chronic expression by other non-manipulated genes sensing blood pressure changes) which can be demonstrated result in an absence of detectable blood pressure changes. This hypothesis and its implications for the genetics of hypertension will be tested by the applicant in five specific aims. The first four aims will investigate the effects on blood pressure of altered expression of f our candidate genes: 1) the renin 1C gene 2) the Agtr1A gene 3) the type A natriuretic peptide receptor gene 4) the natriuretic peptide "clearance" type receptor gene. The final specific aim involves the development of a path diagram displaying the interaction of these genetic determinants from Aims 1-4. This includes predictions and the testing of these predictions using crosses between the mice generated for these studies.

此续签申请的目的是继续在 上一个资助期的重点是分析各种机构的作用 通过控制剂量来控制高血压的候选基因 在基因工程小鼠中。 这项先前的工作涉及使用基因 目标是创造具有零、一、二、三和四拷贝的小鼠 针对其正常染色体位置的候选基因，然后 评估这些明确的改变对高血压的影响 老鼠。 研究表明，基因剂量决定了 这些基因的表达直接影响血液 压力，或由于体内平衡而对血压产生减弱的影响 由其他遗传因素介导的调整。 假设是 从这些先前的研究中发展而来，并将在 拟议的研究是表达水平的变化 多种基因会导致血压变化，这可能是 反映了被操纵基因的表达增加，或者可能是 根据体内平衡的调整，迟钝或完全错过 由其他元素介导。 Smithies 博士解释了这些迟钝的变化 由于稳态调整后虚拟血压发生变化（即） 其他非操纵基因感知血液改变的慢性表达 压力变化），这可以证明导致不存在 可检测到的血压变化。 这个假设及其含义 申请人将分五次进行高血压遗传检测 具体目标。 前四个目标将研究对血液的影响 我们的四个候选基因的表达改变的压力：1) 肾素 1C 基因 2) Agtr1A 基因 3) A 型利钠肽受体基因 4) 利钠肽“清除”型受体基因。 最终的具体目标涉及路径图的开发 显示目标 1-4 中这些遗传决定因素的相互作用。 这包括预测和使用这些预测进行测试 这些研究产生的小鼠之间的杂交。