ANIMAL MODELS FOR STUDYING THE GENETICS OF HYPERTENSION

长期目标是帮助解开基因的复杂性 原发性高血压。基因的预先计划突变很可能是 在高血压病因学中的重要作用 血压、血容量和钠平衡的动态平衡 由基因打靶在动物身上产生，在其他方面保持不变 遗传背景。最初集中在两个多肽激素系统上 在相反的作用下，基因将被修改，以控制供应 或者对这些多肽的反应。具体目标有五个： (I)血管紧张素II(Ang II)，一种具有强烈血管收缩作用的八肽 和保盐作用，被编码为一个大的 前体，血管紧张素原。第一个特定的目标是修改基因 对于血管紧张素原，因此：a)它不产生产物；b)部分 Ang II的编码被改变了，但其余的没有变化。 (Ii)第二个具体目标是使编码基因失活 血管紧张素Ⅱ1型受体在血管平滑肌中的表达 细胞、肾脏和肾上腺。 (Iii)心房利钠因子(ANF)是一种强效的除盐和 其28个氨基酸编码为 大前体的羧基末端(ProANF)。第三个具体目标 是修改proANF的基因，以便：a)它不产生任何产物；b) ANF的部分编码被更改，但其余部分保持不变。 (Iv)第四个具体目标是研究 有计划的突变：a)单个；b)组合。 (V)第五个具体目标是研究突变体的反应 动物对扰乱循环内稳态的操作，包括： A)非侵入性程序(例如，盐摄入量的变化；药理学 药物)；b)通常导致高血压的程序(例如肾脏 动脉夹闭；5/6肾切除)。

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).