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国家许多人的严重健康问题。心房利钠肽（ANP）是一种内源性强有力的利尿激素，具有利尿、利钠、舒张血管和抗增殖作用，是控制血压和心血管稳态的重要因素。鸟苷酸环化酶/利钠肽受体-A（GC-A/NPRA）是参与ANP调节作用的主要位点之一，其结合ANP和鸟苷酸环化酶活性在不同组织中显著不同。然而，Npr 1基因（编码NPRA）的功能表达和调控的分子基础还不清楚。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中建立的Npr 1基因靶向突变小鼠模型研究其生理功能。我们的基本假设是，Npr 1基因表达的情况下，在完整的动物体内呈现出不反对强大的钠保留，血管收缩，促炎和增殖系统，而Npr 1基因的过度表达发挥生理作用，是利钠，血管舒张，抗炎和抗增殖的性质。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，以及整个动物水平的生理信息，从而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，生物化学和病理生理学问题，从而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提供直接检测Npr 1基因剂量和无效突变对ANP/NPRA介导的生物学反应的疗效和影响的方法。在这一领域的研究进展将显着加强和推进我们的遗传和分子方法的知识，以评估Npr 1基因在控制液体容量，血压，充血性心力衰竭，和其他生理功能和病理状态的作用。由此产生的知识将产生新的分子治疗靶点，用于治疗高血压和预防高血压相关的心血管疾病。 公共卫生相关性：高血压是现代世界日益严重的问题。超过6000万美国人患有高血压，这会引发肾脏疾病，心力衰竭和中风。使用Npr 1基因靶向突变小鼠模型，本申请中提出的研究将为利钠肽受体-A在控制血压和高血压中的作用提供新的见解。此外，该研究项目将阐明改变基因功能的分子机制，从而确定有助于治疗和预防高血压及相关心血管疾病的独特分子靶点。从拟议的研究中获得的信息将产生一个更准确的评估心房利钠肽受体基因的整合和保护作用，并进入可能的发病机制，受体介导的心房利钠肽生物活性失调，可能会导致异常的液体容量调节和血压稳态。最终，这些知识将产生新的分子治疗靶点，用于控制和治疗高血压和心血管疾病。

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. PUBLIC HEALTH RELEVANCE: High blood pressure is a growing problem in the modern world. More than 60 million Americans suffer from high blood pressure, which provokes kidney disease, heart failure, and stroke. Using Npr1 gene-targeted mutant mouse models, the research proposed in this application will provide new insights into the role of natriuretic peptide receptor-A in controlling blood pressure and hypertension. Moreover, this research project will elucidate the molecular mechanisms by which altered gene function may identify unique molecular targets that contribute towards the treatment and prevention of hypertension and related cardiovascular diseases. Information gained from the proposed studies will yield a more accurate assessment of the integrative and protective roles of atrial natriuretic peptide receptor gene and into possible mechanisms of pathogenesis whereby malregulation of receptor-mediated atrial natriuretic peptide bioactivity could result in abnormalities of fluid volume regulation and blood pressure homeostasis. Ultimately, this knowledge should yield new molecular therapeutic targets for the control and treatment of hypertension and cardiovascular diseases.