Animal Models for Studying the Genetics of Hypertension

描述(由申请人提供)：我们的长期目标仍然是揭开高血压及其并发症的遗传复杂性。《特殊目的(I)》将检验这样一种假设，即血压是由许多遗传和环境因素控制的，这些因素单独只有很小的影响，但在一些组合中是有害的，在另一些组合中是有益的。将产生在三个不同生理系统中具有高表达和低表达变异(Agtr1a、Npr1和PPARG)的成对组合的小鼠。遥测血压监测和定量RT-PCR将确定饮食中的盐和脂肪以及相关药物治疗对这些小鼠的影响，以及它们心脏、肾脏、肾上腺、肝脏和脂肪组织的动态平衡补偿受到的影响。特殊目的(II)将检验肾外肾素基因对维持血压重要的假说。Ren1c-/-小鼠(在任何地方都不能产生肾素)和转肾素基因的小鼠，RenTgs(只在肝脏产生不同恒定水平的肾素)将交配，他们的Ren1c-/-RenTg后代将被用来确定肾外肾素是否可以调节血压。我们将把Ren1c-/-RenTg小鼠不产生肾素的肾脏移植到野生型小鼠体内，以确定肾外组织中的Ren1c基因是否可以控制血压。特殊目的(III)将检验这一假设，即在高血压心肌肥大期间，心肌细胞呈现两种状态之一：肥大但不表达胎儿基因，或肥大并表达胎儿基因。我们将诱导和逆转表达肥大反应基因荧光指示物的小鼠的高血压，并评估该指示物和其他基因在单个细胞中的表达，以确定基因在单个细胞中是协调切换还是随机切换，以及切换的细胞是否可以恢复到原来的状态。这几项研究将有助于更好地理解遗传因素如何影响血压、血压的动态平衡以及高血压的并发症。

DESCRIPTION (provided by applicant): Our long-term objective remains to unravel the genetic complexities of essential hypertension and its complications. Specific aim (i) will test the hypothesis that blood pressure is controlled by many genetic and environmental factors that individually have only small effects but which in some combinations are detrimental and in others beneficial. Mice having pair-wise combinations of high and low expressing variants at genetic loci (Agtr1a, Npr1, and Pparg) in three different physiological systems will be generated. Telemetric blood pressure monitoring and quantitative RT-PCR will determine the effects on these mice of dietary salt and fat, and of relevant drug treatments, and how homeostatic compensations in their heart, kidneys, adrenals, liver and adipose tissues are affected. Specific aim (ii) will test the hypothesis that the renin gene outside the kidney is important in blood pressure maintenance. Ren1c-/- mice (which cannot produce renin anywhere), and mice with renin transgenes, RenTgs (which produce renin at different constant levels only in the liver) will be mated, and their Ren1c-/-RenTg progeny will be used to determine whether extra-renal renin can regulate blood pressure. We will transplant non-renin-producing kidneys from Ren1c-/-RenTg mice into wildtype mice to determine whether the Ren1c gene in extra-renal tissues, but not in the kidney, can control blood pressure. Specific aim (iii) will test the hypothesis that, during hypertensive cardiac hypertrophy, myocytes assume one of two states: hypertrophic but not expressing fetal genes, or hypertrophic and expressing fetal genes. We will induce and reverse hypertension in mice expressing fluorescent indicators of hypertrophy-responsive genes, and assess expression of the indicator and other genes in individual cells to determine whether genes switch concordantly or randomly in individual cells, and whether switched cells can resume their former state. Together these several studies should contribute to a better understanding of how genetic factors affect blood pressure, its homeostasis, and the complications of hypertension.