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）：高血压和心血管疾病对于工业化世界中的许多人来说都是严重的健康问题。心房利尿肽（ANP）是一种内源性且有效的低血压激素，可引起亚钠，利尿剂，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。 ANP调节作用的主要基因座之一是Guanylyl Cyclase/natriate肽受体-A（GC-A/NPRA），其ANP结合和Guanylyl Cyclase活性在不同的组织中差异很大。但是，尚不清楚NPR1基因（编码NPRA）功能表达和调节的分子基础。为了进一步了解NPRA扮演的生物学作用，我们将使用以NPR1基因靶向突变小鼠模型来研究生理功能，这是我们在设施中确定的。我们的基本假设是，在体内完整动物中缺乏NPR1基因表达，这使得无反对的强大钠钠，血管收缩，促炎和增殖系统的无反抗。而NPR1基因的过表达产生的生理作用，这些作用是纳西脂，血管舒张，抗炎和抗增生性本质上的。为了实现该建议的目标，我们将在分子水平上将遗传信息与细胞水平的生化信息以及整个动物水平的生理信息整合在一起，从而导致垂直整合的分子生理策略。我们将利用分子遗传学技术的能力来回答体内完整动物中细胞，生化和病理生理问题，以得出确定的结论，这些结论在生理上相关。从上述研究线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介导的生物学反应的疗效和影响的手段。在这一研究领域的进展将显着增强和提高我们对遗传和分子方法的了解，以评估NPR1基因在控制液体体积，血压，充血性心力衰竭以及其他生理功能和病理状态的作用中的作用。所得的知识应产生新的分子治疗靶标，以治疗高血压和预防与高血压相关的心血管疾病。 公共卫生相关性：高血压是现代世界中日益增长的问题。超过6000万美国人患有高血压，这会引起肾脏疾病，心力衰竭和中风。使用NPR1基因靶向的突变小鼠模型，本应用中提出的研究将提供新的见解，以了解Natriuretic肽受体A在控制血压和高血压中的作用。此外，该研究项目将阐明基因功能改变的分子机制可以确定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标。从拟议的研究中获得的信息将更准确地评估心房纳第二肽受体基因的整合和保护作用，并成为发病机理的可能机制，从而导致受体介导的心房纳托氏尿素生物活性发生破坏，从而导致流化体积和血液压力正常和血液压力正常的异常。最终，这些知识应产生新的分子治疗靶标，以控制和治疗高血压和心血管疾病。