Role of Apelin in the Systemic and Pulmonary Vasculature

Apelin 在全身和肺血管中的作用

• 批准号: 7920245
• 负责人: Hyung Joon Chun
• 金额: $ 13.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920245
• 关键词: Advisory Committees; Angiotensin II; Angiotensins; Animal Model; Apolipoprotein E; Atherosclerosis; Biological; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Credentialing; Data; Disease; Elements; Endothelium; Equilibrium; Functional disorder; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Goals; Homeostasis; Infusion procedures; Instruction; Knowledge; Lead; Ligands; Lung; Maintenance; Mediating; Medicine; Mentors; Modeling; Molecular; Mus; Nitric Oxide; Pathologic; Pathologic Processes; Pathway interactions; Patients; Peptide Signal Sequences; Physiology; Play; Process; Production; Property; Pulmonary Hypertension; Pulmonary artery structure; Receptor, Angiotensin, Type 1; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stress; Structure; Techniques; Therapeutic; Training Programs; Vascular Endothelial Cell; Work; abstracting; career; computerized data processing; insight; mouse model; novel; novel therapeutics; pressure; protective effect; receptor; receptor internalization; skills; trafficking; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): PROJECT SUMMARY: This proposal describes a five year training program to develop a career in academic cardiovascular medicine. The applicant will aim to obtain the credentials and funding support necessary to achieve independence as an investigator, with the long term career goals to provide insights into novel signaling processes that are essential to vascular physiology and pathophysiology. The goals of the applicant over the next five years will be to master additional experimental techniques, enhance knowledge of molecular biological concepts, and develop administrative skills necessary to conduct independent research. With the guidance from his mentor, Dr. Thomas Quertermous, as well as carefully selected panel of Advisory Committee of senior investigators, the applicant will receive sufficient support to achieve these goals. Project Description: G-protein coupled receptor (GPCR) signaling plays an important role in regulation of cardiovascular pathologic processes. APJ is a GPCR with a 31% homology to the angiotensin II type 1 receptor. Its ligand apelin is a potent inotrope with vasodilatory properties that are in part mediated by nitric oxide. Our recent findings have demonstrated inhibition of angiotensin II signaling by the apelin-APJ pathway, leading to near complete abrogation of angiotensin ll-mediated atherosclerosis. In addition, we have identified high expression of apelin and APJ in the pulmonary vasculature. Significant modulation of apelin and APJ expression also occurs in patients and animal models of pulmonary hypertension, suggesting a yet to be defined role of apelin in the pulmonary vasculature. Moreover, our work with the APJ deficient mice demonstrate significantly elevated pulmonary artery pressures, suggesting an important role in the pulmonary vascular homeostasis. In this proposal we seek to further define the role of apelin signaling in both systemic and pulmonary vasculature. We hypothesize that the apelin-APJ pathway plays a critical role in these structures, and that modulation of apelin signaling may serve a role in inhibiting disease processes involving the vasculature such as atherosclerosis and pulmonary hypertension. Our specific aims include: 1) characterization of the apelin-APJ signaling pathway in mouse model of atherosclerosis, 2) determining the role of the apelin-APJ signaling pathway in pulmonary vascular wall disease, and 3) characterization of the crosstalk between the apelin-APJ pathway and angiotensin II pathway. The proposed studies will extend our understanding of the apelin-APJ pathway, and provide further insights into the potential therapeutic benefits of this pathway in vascular wall disease. RELEVANCE (See instructions): Apelin is a recently discovered signaling peptide. Our recent data demonstrate a potent protective role of apelin signaling against pathologic stress that mediates vascular wall disease. Elucidating the role of apelin in vascular wall signaling may lead to novel therapeutic strategies to target disease processes such as atherosclerosis and pulmonary hypertension. (End of Abstract)

描述(由申请人提供)：项目概要：本建议书描述了一项旨在发展心血管医学学术生涯的五年培训计划。申请者将致力于获得必要的资历和资金支持，以实现作为一名研究人员的独立性，长期职业目标是提供对血管生理学和病理生理学至关重要的新信号过程的见解。申请者在未来五年的目标将是掌握更多的实验技术，增强分子生物学概念的知识，并发展进行独立研究所需的管理技能。在他的导师Thomas Querterous博士的指导下，以及精心挑选的高级调查咨询委员会小组的指导下，申请人将获得足够的支持，以实现这些目标。项目简介：G蛋白偶联受体信号转导系统在心血管病理过程中起着重要的调节作用。APJ是一种与血管紧张素II 1型受体有31%同源性的GPCR。它的配体apelin是一种强大的肌松药，具有部分由一氧化氮介导的血管扩张特性。我们最近的发现表明，通过apelin-APJ通路抑制血管紧张素II信号，导致血管紧张素II介导的动脉粥样硬化几乎完全消除。此外，我们还发现APELIN和APJ在肺血管中高表达。APELIN和APJ表达的显著调节也出现在患者和动物模型中，提示APELIN在肺血管系统中的作用尚不明确。此外，我们对APJ缺陷小鼠的研究显示，肺动脉压显著升高，这表明在肺血管动态平衡中起着重要作用。在这项建议中，我们试图进一步确定apelin信号在全身和肺血管系统中的作用。我们假设apelin-APJ通路在这些结构中起关键作用，并且apelin信号的调节可能在抑制涉及血管系统的疾病过程中发挥作用，如动脉粥样硬化和肺动脉高压。我们的具体目标包括：1)研究apelin-APJ信号通路在小鼠动脉粥样硬化模型中的作用；2)确定apelin-APJ信号通路在肺血管壁疾病中的作用；3)鉴定apelin-APJ信号通路与血管紧张素II通路之间的相互作用。拟议的研究将扩大我们对apelin-APJ途径的理解，并为该途径在血管壁疾病中的潜在治疗益处提供进一步的见解。相关性(参见说明)：apelin是一种新近发现的信号肽。我们最近的数据表明，apelin信号对介导血管壁疾病的病理性应激具有强大的保护作用。阐明apelin在血管壁信号转导中的作用可能导致针对动脉粥样硬化和肺动脉高压等疾病过程的新的治疗策略。(摘要结束)