Integrative Cardiovascular Biology of Apelin-APJ

描述(由申请人提供)： 这一职业发展奖将促进候选人转变为斯坦福大学心血管内科的独立研究员和内科科学家。通过接触：o一流的科学环境，与国际知名导师的互动，以及与杰出的咨询委员会的咨询，候选人有望拓宽他的科学技能集，并实现他作为心力衰竭和心脏功能领域的综合心血管生物学家的独立目标。这些实验计划建立在已经发表的材料的基础上，旨在测试早期工作提出的机械假说。2003年，候选人首次描述了apelin-APJ在心血管健康和疾病中的作用。描述apelin体内生理学的后续研究揭示了一种高度保守且具有治疗前景的神经激素系统。在本文提出的工作中，将结合细胞培养、分离的心肌细胞缩短和活体技术来确定心肌APJ受体结合调节心肌收缩和肥大的信号机制。为了确定最终的效应机制，将探索心肌APJ受体的亚细胞位置、其G蛋白偶联及其邻近的信号伙伴(特定目标1)。旁分泌、内分泌和自分泌过程对Apelin综合心血管效应的贡献将通过在小鼠体内和在共培养细胞中的组织特异性、条件性基因缺失来阐明(特定目标2)。最后，apelin在细胞能量学中的作用将通过分离的心脏核磁共振波谱和直接测量皮肤肌肉纤维中的氧化磷酸化来确定(特定目标3)。APELIN-APJ系统对液体平衡、心脏负荷和收缩储备有积极的作用，是治疗心力衰竭的药物操作的有力候选者。这里描述的实验将为未来将这一工作转移到临床领域提供一个良好的机制基础。(摘要结束)

DESCRIPTION (provided by applicant): This career development award will facilitate the transition of the candidate to independent investigator and physician-scientist within the Division of Cardiovascular Medicine at Stanford University. Through exposure :o a first class scientific environment, interaction with an internationally renowned mentor, and consultation with an outstanding advisory committee, the candidate is expected to broaden his scientific skill set and reach his goal of independence as an integrative cardiovascular biologist in the field of heart failure and cardiac function. The experiments planned build on material already published and aim to test mechanistic hypotheses suggested by the earlier work. The role of apelin-APJ in cardiovascular health and disease was first described by the candidate in 2003. Follow up investigations describing the in vivo physiology of apelin revealed a highly conserved and therapeutically promising neurohormonal system. In the work proposed here, signaling mechanisms by which myocardial APJ receptor binding regulates cardiac contractility and hypertrophy will be identified using a combination of cell culture, isolated myocyte cell shortening and in vivo techniques. The subcellular location of the myocardial APJ receptor, its G protein coupling, and its proximate signaling partners will be explored in order to identify ultimate effector mechanisms (Specific aim 1). The contribution of paracrine, endocrine and autocrine processes to the integrated cardiovascular effects of apelin will be elucidated using tissue specific, conditional gene deletion in mice, in vivo and in co-cultured cells (Specific aim 2). Finally, the role of apelin in cellular energetics will be determined through isolated heart nuclear magnetic resonance spectroscopy and direct measurement of oxidative phosphorylation in skinned muscle fibers (Specific aim 3). The apelin-APJ system is a compelling candidate for pharmacological manipulation in the treatment of heart failure due to positive effects on fluid balance, cardiac load and contractile reserve. The experiments described herein will provide a sound mechanistic basis for the future translation of this body of work to the clinical domain. (End of Abstract)