Role of Apelin in the Systemic and Pulmonary Vasculature

项目概述：本提案描述了一个为期五年的培训计划，以发展学术心血管医学事业。申请人将致力于获得独立研究者所需的证书和资金支持，其长期职业目标是对血管生理学和病理生理学至关重要的新信号过程提供见解。申请者在未来五年内的目标是掌握更多的实验技术，提高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 Quertermous博士的指导下，以及精心挑选的高级研究人员咨询委员会小组，申请人将获得足够的支持来实现这些目标。项目描述：g蛋白偶联受体（GPCR）信号在心血管病理过程的调控中起重要作用。APJ是一种与血管紧张素II型1受体具有31%同源性的GPCR。它的配体尖蛋白是一种有效的收缩物，具有血管舒张特性，部分由一氧化氮介导。我们最近的研究结果表明，apelin-APJ通路抑制血管紧张素II信号，导致血管紧张素介导的动脉粥样硬化几乎完全消失。此外，我们在肺血管中发现了apelin和APJ的高表达。肺动脉高压患者和动物模型中也出现了apelin和APJ表达的显著调节，提示apelin在肺血管系统中的作用尚不明确。此外，我们对APJ缺陷小鼠的研究表明，APJ显著升高了肺动脉压，这表明APJ在肺血管稳态中起重要作用。在这一建议中，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起作用，如动脉粥样硬化和肺动脉高压。我们的具体目标包括：1)表征动脉粥样硬化小鼠模型中的apelin-APJ信号通路；2)确定apelin-APJ信号通路在肺血管壁疾病中的作用；3)表征apelin-APJ通路与血管紧张素II通路之间的串扰。这些研究将扩展我们对apelin-APJ通路的理解，并进一步了解该通路在血管壁疾病中的潜在治疗益处。相关性：Apelin是最近发现的一种信号肽。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在血管壁信号传导中的作用可能会导致针对动脉粥样硬化和肺动脉高压等疾病过程的新治疗策略。（摘要结束）

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)