Study of ANP Receptor: Gene Targeting and Expression

描述（由申请人提供）：高血压和心血管疾病是工业化世界中许多人的严重健康问题。心房利钠肽（ANP）是一种内源性有效的降压激素，具有利钠、利尿、血管舒张和抗增殖作用，是控制血压和心血管稳态的重要因素。参与ANP调控作用的主要基因座之一是观嘌呤环化酶/利钠肽受体- a (GC-A/NPRA)，其ANP结合和观嘌呤环化酶活性在不同组织中差异显著。然而，Npr1基因（编码NPRA）的功能表达和调控的分子基础尚不清楚。为了进一步了解NPRA发挥的生物学作用，我们将使用我们在我们的设施建立的Npr1基因靶向突变小鼠模型来研究其生理功能。我们的基本假设是，在体内完整动物中缺乏Npr1基因表达，会产生强大的钠潴留、血管收缩、促炎和增殖系统；然而，Npr1基因的过度表达在本质上具有尿钠、血管扩张、抗炎和抗增殖的生理作用。为了实现本提案的目标，我们将整合分子水平的遗传信息、细胞水平的生化信息和整个动物水平的生理信息，形成垂直整合的分子生理策略。我们将利用分子遗传学技术的力量来回答完整动物体内的细胞、生化和病理生理问题，从而得出明确的和生理学相关的结论。从上述调查中获得的信息将为直接测试Npr1基因剂量和零突变对ANP/ npra介导的生物反应的功效和影响提供手段。这一研究领域的进展将大大加强和推进我们对遗传和分子方法的认识，以评估Npr1基因在控制体液量、血压、充血性心力衰竭和其他生理功能和病理状态中的作用。由此产生的知识将为治疗高血压和预防高血压相关心血管疾病提供新的分子治疗靶点。

DESCRIPTION (provided by applicant): Hypertension and cardiovascular diseases are serious health problems for many individuals in the industrialized world. Atrial natriuretic peptide (ANP) is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and antiproliferative effects, important factors in the control of blood pressure and cardiovascular homeostasis. One of the principal loci involved in the regulatory action of ANP is the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), whose ANP-binding and guanylyl cyclase activities vary remarkably in different tissues. However, the molecular basis of the functional expression and regulation of Npr1 gene (coding for NPRA) are not well understood. To further understand the biological role(s) played by NPRA, we will study the physiological function(s) using Npr1 gene-targeted mutant mouse models, which we have established at our facility. Our fundamental hypothesis is that the absence of Npr1 gene expression in intact animals in vivo renders unopposed powerful sodium-retaining, vasoconstrictive, proinflammatory, and proliferative systems; whereas, overexpression of Npr1 gene exerts physiological effects that are natriuretic, vasodilatory, anti-inflammatory, and antiproliferative in nature. To accomplish the objective of this proposal, we will integrate genetic information at the molecular level, with biochemical information at the cellular level, and physiological information at the whole-animal level, resulting in a vertically integrated molecular-physiological strategy. We will exploit the power of molecular genetics techniques to answer cellular, biochemical, and pathophysiological questions in intact animals in vivo so as to arrive at conclusions that are definitive and physiologically relevant. The information obtained from the above lines of investigation will provide the means to test directly the efficacy and impact of Npr1 gene dosage and null mutation on ANP/NPRA-mediated biological responses. Progress in this field of research will significantly strengthen and advance our knowledge of genetic and molecular approaches to evaluate the role of Npr1 gene in the control of fluid volume, blood pressure, congestive heart failure, and other physiological function(s) and pathological states. The resulting knowledge should yield new molecular therapeutic targets for the treatment of hypertension and prevention of hypertension-related cardiovascular disorders.