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)将测试血压由许多遗传和环境因素控制的假设，这些因素单独影响很小，但在某些组合中是有害的，而在其他组合中是有益的。在三种不同的生理系统中，将产生具有基因位点（Agtr1a， Npr1和Pparg）高表达和低表达变体成对组合的小鼠。遥测血压监测和定量RT-PCR将确定饮食盐和脂肪以及相关药物治疗对这些小鼠的影响，以及它们的心脏、肾脏、肾上腺、肝脏和脂肪组织的稳态代偿是如何受到影响的。特异性目的（ii）将验证肾外肾素基因在血压维持中起重要作用的假设。将Ren1c-/-小鼠（不能在任何地方产生肾素）和肾素转基因小鼠RenTgs（仅在肝脏中产生不同恒定水平的肾素）进行配对，并使用它们的Ren1c-/- rentg后代来确定肾外肾素是否可以调节血压。我们将Ren1c-/- rentg小鼠的不产生肾素的肾脏移植到野生型小鼠体内，以确定肾外组织而非肾脏中的Ren1c基因是否能控制血压。特异性目的（iii）将检验假设，在高血压心脏肥厚期间，肌细胞呈现两种状态之一：肥厚但不表达胎儿基因，或肥厚但表达胎儿基因。我们将在表达肥大反应基因荧光指示剂的小鼠中诱导和逆转高血压，并评估该指示剂和其他基因在单个细胞中的表达情况，以确定基因在单个细胞中是一致开关还是随机开关，以及开关后的细胞是否能恢复到原来的状态。综上所述，这几项研究应该有助于更好地理解遗传因素如何影响血压、血压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.