BLRD Research Career Scientist Award Application

我的研究的总体目标是了解慢性炎症的病理生理学机制， 在一些实施方案中，本发明的组合物用于治疗疾病，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，并确定新的药物筛选和临床治疗的目标。我们应用综合 包括单分子分析、活细胞成像、基因组和蛋白质组分析的方法，以及 转基因模型动物，以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，我一直受到NIH，VA和 私人机构我目前得到了两个NIH R 01赠款，一个VA优秀奖和一个联合加州 TRDRP赠款。我实验室的结果大大加深了我们对信号的理解 为HF和AD的治疗提供了新的靶点。通过这些努力，我得到了一个 AHA于2010年设立了研究者奖，并确立了自己作为心脏信号传导领域全球领导者的地位 转导 早期主要研究心脏β-肾上腺素能受体（bAR）的新特性 信号传导，如心脏收缩功能中cAMP-PKA级联的时空调节。过去 10年来，我扩大了我的研究计划，以了解疾病中的调节信号网络 在慢性条件下，如炎症和代谢紊乱的发展。其中一个亮点是 我们已经描述了一种胰岛素受体（InsR）和b2 AR的膜蛋白复合物，在大肠杆菌中广泛表达。 不同的组织b2 AR和InsR的激活是心血管功能的重要调节机制， 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 HF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途径， 并发症和与糖尿病和代谢综合征相关的神经退行性疾病。几 下面的活动项目得到了NIH和VA的持续资助。目前的退伍军人事务部奖学金旨在 表征两种蛋白GRK 5和SAP 97在肾上腺素减少（脱敏）中的重要作用 刺激信号分子一氧化氮以增强心输出量。我们会发现这一规定是如何进行的 心脏病中的错误，从而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.