Study of ANP Receptor: Gene Targeting and Expression

描述(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。心钠素(ANP)是一种内源性、强效的降压激素，具有利钠、利尿、血管松弛和抗增殖作用，是控制血压和心血管内环境稳定的重要因素。参与心钠素调节作用的主要位点之一是鸟苷酰环化酶/利钠肽受体A(GC-A/NPRA)，其心钠素结合和鸟苷酸环化酶在不同组织中的活性存在显著差异。然而，Npr1基因(编码NPRA)功能表达和调控的分子基础还不是很清楚。为了进一步了解NprA的生物学作用(S)，我们将利用我们在本研究所建立的Npr1基因靶向突变小鼠模型来研究Npr1的生理功能(S)。我们的基本假设是，在完整的动物体内，Npr1基因的缺失使强大的钠保留、血管收缩、促炎和增殖系统不受对抗；而Npr1基因的过度表达在本质上发挥了利钠、血管扩张、抗炎和抗增殖的生理效应。为了实现这一建议的目标，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，从而形成一个垂直整合的分子-生理策略。我们将利用分子遗传学技术的力量，在活体内回答完整动物的细胞、生化和病理生理学问题，以得出明确的和生理相关的结论。从上述研究中获得的信息将为直接测试Npr1基因剂量和零突变对ANP/NPRA介导的生物学反应的有效性和影响提供手段。这一领域的研究进展将大大加强和推进我们对Npr1基因在控制液体量、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的遗传学和分子方法的了解(S)。由此产生的知识应该会为高血压的治疗和预防高血压相关的心血管疾病产生新的分子治疗目标。

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.