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示原发性高血压及其并发症的遗传复杂性。具体目标（i）将检验血压受许多遗传和环境因素控制的假设，这些因素单独只有很小的影响，但在某些组合中是有害的，而在其他组合中是有益的。将产生在三种不同生理系统中在遗传基因座（Agtr1a、Npr1和Pparg）处具有高表达变体和低表达变体的成对组合的小鼠。遥测血压监测和定量RT-PCR将确定饮食中的盐和脂肪对这些小鼠的影响，以及相关的药物治疗，以及它们的心脏、肾脏、肾上腺、肝脏和脂肪组织中的稳态补偿如何受到影响。具体目标（ii）将测试肾脏外的肾素基因在血压维持中很重要的假设。Ren1c-/-小鼠（在任何地方都不能产生肾素）和具有肾素转基因的小鼠，RenTgs（仅在肝脏中以不同的恒定水平产生肾素）将被交配，它们的Ren1c-/-RenTg后代将被用于确定肾外肾素是否可以调节血压。我们将从Ren1c-/-RenTg小鼠中移植不产生肾素的肾脏到野生型小鼠中，以确定肾外组织中的Ren1c基因（而不是肾脏中的）是否可以控制血压。具体目标（iii）将测试的假设，在高血压心脏肥大，心肌细胞假设两种状态之一：肥大，但不表达胎儿基因，或肥大和表达胎儿基因。我们将在表达肥大反应基因的荧光指示剂的小鼠中诱导和逆转高血压，并评估指示剂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否一致或随机转换，以及转换的细胞是否可以恢复其以前的状态。这几项研究将有助于更好地了解遗传因素如何影响血压，其稳态和高血压并发症。

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.