ANIMAL MODELS FOR STUDYING THE GENETICS OF HYPERTENSION

研究高血压遗传学的动物模型

• 批准号: 2225413
• 负责人: OLIVER SMITHIES
• 金额: $ 47.87万
• 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 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2225413
• 关键词: angiotensin II; atrial natriuretic peptide; blood volume; dietary sodium; disease /disorder model; familial hypertension; genetic recombination; homeostasis; laboratory mouse; model design /development; mutant; phenotype; polymerase chain reaction; salt intake

The long term-objective is to help unravel the genetic complexities of essential hypertension. Pre-planned mutations in genes likely to be important in the etiology of essential hypertension and in the homeostasis of blood pressure, blood volume and sodium balance will be generated by gene targeting in animals having an otherwise constant genetic background. Centering initially on two peptide hormone systems with opposing effects, genes will be modified that control the supply of or the response to the peptides. There are five specific aims: (i) Angiotensin II (ANG II), an octapeptide with potent vasoconstrictive and salt-retaining effects, is coded as the amino-terminus of a large precursor, angiotensinogen. The first specific aim is to modify the gene for angiotensinogen so that: a) it makes no product; b) the portion coding for ANG II is altered, but the rest is unchanged. (ii) The second specific aim is to inactivate the gene coding for the type 1 receptor of ANG II, which is expressed in vascular smooth muscle cells, kidneys and adrenals. (iii) Atrial natriuretic factor (ANF) is a potent salt-eliminating and smooth muscle relaxing peptide; its 28 amino acids are coded as the carboxy terminus of a large precursor (proANF). The third specific aim is to modify the gene for proANF so that: a) it makes no product; b) the portion coding for ANF is altered but the rest is unchanged. (iv) The fourth specific aim is to study the phenotypes generated by the planned mutations: a) singly; and b) in combinations. (v) The fifth specific aim is to study the responses of the mutant animals to manipulations that disturb circulatory homeostasis, including: a) non-invasive procedures (e.g. changes in salt intake; pharmacological agents); b) procedures that normally lead to hypertension (e.g. renal artery clipping; 5/6 renal ablation).

长期目标是帮助解开遗传的复杂性， 原发性高血压 预先计划的基因突变可能是 在原发性高血压的病因学和 血压、血容量和钠平衡的体内平衡将 通过在动物中的基因靶向产生， 遗传背景 最初以两个肽激素系统为中心 相反的影响，基因将被修改，控制供应， 或者对肽的反应。 有五个具体目标： (i)血管紧张素II（ANG II）是一种具有强血管收缩作用的八肽， 和盐的保留作用，被编码为一个大的氨基末端， 前体血管紧张素原。 第一个具体目标是修改基因 对于血管紧张素原，以便：a）它不产生任何产品; B）该部分 ANG II的编码发生了变化，但其余部分保持不变。 (ii)第二个具体目标是将编码 血管紧张素II的1型受体，表达于血管平滑肌 细胞、肾脏和肾上腺。 (iii)心房利钠因子（ANF）是一种有效的排盐和 平滑肌松弛肽;其28个氨基酸编码为 大前体（proANF）的羧基末端。 第三个具体目标 是修饰proANF的基因，使得：a）它不产生产物; B） ANF的部分编码被改变，但其余部分不变。 (iv)第四个具体目标是研究由基因组产生的表型。 计划突变：a）单独;和B）组合。 (v)第五个具体目标是研究突变体的反应 对动物进行扰乱循环稳态的操作，包括： a）非侵入性程序（例如，盐摄入量的变化;药理学 B）通常导致高血压的程序（例如肾性高血压） 动脉夹闭; 5/6例肾消融）。