Study of ANP Receptor: Gene Targeting and Expression

ANP受体的研究：基因打靶和表达

• 批准号: 8270016
• 负责人: Kailash N Pandey
• 金额: $ 37.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270016
• 关键词: Affect; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Applications Grants; Atrial Natriuretic Factor; Atrial Natriuretic Factor Receptors; Binding; Biochemical; Biological; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Code; Collaborations; Congestive Heart Failure; Diet; Distal; Diuretics; Dose; Functional disorder; Gene Dosage; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Techniques; Glomerular Filtration Rate; Guanylate Cyclase; Health; Heart failure; Homeostasis; Hormones; Hypertension; Individual; Injury; Investigation; Juxtaglomerular Cell; Kidney; Kidney Diseases; Knowledge; Liquid substance; Matrix Metalloproteinases; Mediating; Mitogen-Activated Protein Kinases; Molecular; Molecular Genetics; Molecular Target; Mus; Mutant Strains Mice; NF-kappa B; Nature; Nephrons; North Carolina; Pathogenesis; Physiological; Play; Property; Proteins; Receptor Gene; Regulation; Renal Plasma Flow; Renal function; Renin; Renin-Angiotensin System; Research; Research Project Grants; Role; Signal Transduction; Sodium; Sodium Chloride; Stroke; System; Testing; Tissues; Universities; atrial natriuretic factor receptor A; base; blood pressure regulation; cell type; cytokine; duplicate genes; gene function; homologous recombination; hypertension prevention; hypertension treatment; in vivo; insight; knockout gene; knowledge of results; mutant mouse model; null mutation; overexpression; public health relevance; receptor; response; saluretic; therapeutic target

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.

描述（由申请人提供）：对于工业化国家的许多人来说，高血压和心血管疾病是严重的健康问题。心房钠尿肽 (ANP) 是一种内源性强效降血压激素，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 调节作用的主要位点之一是鸟苷酸环化酶/利钠肽受体-A (GC-A/NPRA)，其 ANP 结合和鸟苷酸环化酶活性在不同组织中存在显着差异。然而，Npr1 基因（编码 NPRA）功能表达和调控的分子基础尚不清楚。为了进一步了解 NPRA 所发挥的生物学作用，我们将使用我们在我们的设施中建立的 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，完整动物体内 Npr1 基因表达的缺失会导致强大的钠潴留、血管收缩、促炎和增殖系统不受对抗；而Npr1基因的过度表达则发挥排尿钠、血管舒张、抗炎和抗增殖等生理作用。为了实现该提案的目标，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，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、生化和病理生理学问题，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测试 Npr1 基因剂量和无效突变对 ANP/NPRA 介导的生物反应的功效和影响的方法。这一研究领域的进展将显着加强和推进我们对遗传和分子方法的了解，以评估 Npr1 基因在控制体液量、血压、充血性心力衰竭以及其他生理功能和病理状态中的作用。由此产生的知识应该会产生治疗高血压和预防高血压相关心血管疾病的新分子治疗靶点。 公共卫生相关性：高血压是现代世界一个日益严重的问题。超过 6000 万美国人患有高血压，高血压会引发肾病、心力衰竭和中风。使用 Npr1 基因靶向突变小鼠模型，本申请中提出的研究将为利尿钠肽受体 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可能识别有助于治疗和预防高血压和相关心血管疾病的独特分子靶点的分子机制。从拟议研究中获得的信息将更准确地评估心房钠尿肽受体基因的整合和保护作用，并了解可能的发病机制，受体介导的心房钠尿肽生物活性的失调可能导致体液容量调节和血液异常压力稳态。最终，这些知识应该产生用于控制和治疗高血压和心血管疾病的新分子治疗靶点。