BLRD Research Career Scientist Award Application

本研究的总体目标是了解慢性阻塞性肺疾病的病理生理机制。 疾病，特别是心力衰竭(HF)和阿尔茨海默病(AD)。我的目标是发现未知，建立 新的范例，并确定药物筛选和临床治疗的新靶点。我们综合应用 方法包括单分子分析、活细胞成像、基因组和蛋白质组分析，以及 转基因模型动物了解细胞内信号网络的基本原理及其功能 在疾病发展中的作用。在过去的16年里，我不断地从美国国立卫生研究院、弗吉尼亚州和 私人机构。我目前得到了两项NIH R01拨款、一项退伍军人事务部优异奖和一项联合加州奖的支持 TRDRP赠款。我的实验室的结果极大地加深了我们对信号的理解 为心衰和阿尔茨海默病提供了新的治疗靶点。通过这些努力，我收到了一份 AHA在2010年设立了研究员奖，并确立了自己在心脏信号方面的全球领导者地位 转导。 早年，我的研究主要集中在心脏β-肾上腺素能受体(Bar)的新特性上。 CAMP-PKA时空调控等信号在心脏收缩功能中发挥级联作用。在过去的时间里 10年来，我扩大了我的研究项目，以了解疾病中的调控信号网络 在慢性条件下发展，如炎症和代谢紊乱。其中一个亮点是 我们已经描述了一种由胰岛素受体(InsR)和B2AR组成的膜蛋白复合体，在 不同的组织。B2AR和InsR的激活是两种心血管功能的关键调节机制 和新陈代谢。这些受体还调节认知功能，包括记忆和学习、疼痛、情绪 以及中枢神经系统的压力。这些受体信号通路的失调与 高频和AD的发展。我们最近的研究为了解心血管疾病开辟了一条令人兴奋的道路 与糖尿病和代谢综合征相关的并发症和神经退行性疾病。几个 以下正在进行的项目得到了美国国立卫生研究院和退伍军人事务部的持续资助。目前的退伍军人管理局奖励金旨在 GRK5和SAP97蛋白在肾上腺素还原(脱敏)中的重要作用 刺激信号分子一氧化氮以增加心输出量。我们将看看这项规定是如何进行的 在心脏病方面是错误的，因此提供了治疗心脏病的新策略。

The overall goal of my research is to understand mechanisms underlying pathophysiology in chronic diseases, in particular heart failure (HF) and Alzheimer’s disease (AD). I aim to discover unknowns, establish new paradigms, and identify novel targets for drug screening and clinical therapy. We apply integrative approaches that include single molecule analysis, live-cell imaging, genomic and proteomic analysis, and transgenic model animals to understand the fundamentals of intracellular signaling networks and their functional roles in development of diseases. Over the past 16 years, I have received continuous funding from NIH, VA, and private agencies. I am currently supported by two NIH R01 grants, a VA merit award, and a joint California TRDRP grant. The results from my laboratory have significantly deepened our understanding of signaling regulation and offered novel therapeutic targets for HF and AD. Through these endeavors, I have received an AHA established investigator award in 2010 and established myself as a global leader in cardiac signaling transduction. In the early years, my research focuses on novel features of cardiac beta-adrenergic receptor (bAR) signaling such as spatiotemporal regulation of cAMP-PKA cascades in cardiac contractile function. Over the past 10 years, I have expanded my research program to understand regulatory signaling networks in disease development under chronic conditions such as inflammation and metabolic disorders. One of the highlights is that we have described a membrane protein complex of insulin receptor (InsR) and b2AR broadly expressed in different tissues. Activation of b2AR and InsR are critical regulatory mechanisms of both cardiovascular function and metabolism. These receptors also modulate cognitive function including memory and learning, pain, emotion and stress in the central nerve system. Dysregulation of these receptor signaling pathways has been linked to development of HF and AD. Our recent studies have opened an exciting avenue in understanding cardiovascular complications and neurodegenerative diseases associated with diabetes and metabolic syndromes. Several active projects below are supported by ongoing funding from NIH and VA. The current VA merit grant aims to characterize the essential roles of two proteins GRK5 and SAP97 in reduction (desensitization) of adrenaline stimulation of a signaling molecule nitric oxide to enhance cardiac output. We will find how this regulation goes wrong in heart diseases and thus offers novel strategies to treat heart diseases.