BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10513328
负责人：
YANG K XIANG
金额：
--
依托单位：
VA NORTHERN CALIFORNIA HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513328
关键词：
ADRBK1 gene Adrenergic Agents Adrenergic Receptor Alzheimer&apos s Disease Amyloid beta-Protein Angiotensins Animal Model Asthma Atrial Fibrillation Award Biosensor Brain California Cardiac Cardiac Myocytes Cardiac Output Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell physiology Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Circulation Clinical Clinical Trials Cognition Collaborations Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP DLG1 gene Data Depressed mood Development Diabetes Mellitus Disease Drug Screening EFRAC Emotions Epinephrine Fibrosis Functional disorder Funding GRK5 gene Genes Genetic Genomics Goals Grant Health Health Care Costs Heart Diseases Heart failure Homeostasis Hormones Human Hyperglycemia Hyperinsulinism Impairment Inflammation Inflammatory Insulin Insulin Receptor Interleukin-1 beta Intervention Investigation Joints Laboratories Learning Link Longevity Membrane Proteins Memory Memory Loss Mentors Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Molecular Target Muscle Cells Nature Nerve Neurodegenerative Disorders Neurohormones Neurons Nitric Oxide Outcome Pain Parkinson Disease Pathogenesis Pathologic Pathway interactions Patient Care Patients Pharmaceutical Preparations Physicians Prevention strategy Privatization Prostaglandins Proteins Proteomics Protocols documentation Quality of life Receptor Signaling Regulation Research Research Personnel Role Science Scientist Services Signal Induction Signal Pathway Signal Transduction Signaling Molecule Stress Synapses System Therapeutic Therapeutic Intervention Tissues Transgenic Model Translating United States National Institutes of Health Veterans alpha synuclein beta-2 Adrenergic Receptors beta-adrenergic receptor biochemical tools career clinical practice cognitive function comorbidity cytokine desensitization diabetic diabetic patient flexibility heart function hormone regulation improved inhibitor insight insulin signaling interest live cell imaging military veteran neurotoxicity new therapeutic target novel novel strategies novel therapeutic intervention programs protein complex receptor response single molecule spatiotemporal synuclein

项目摘要

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.

我的研究的总体目标是了解慢性病理生理的基础机制疾病，特别是心力衰竭（HF）和阿尔茨海默氏病（AD）。我的目标是发现未知数，建立新的范式，并确定用于药物筛查和临床疗法的新靶标。我们应用集成包括单分子分析，活细胞成像，基因组和蛋白质组学分析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年中，我收到了NIH，弗吉尼亚州的持续资金，私人机构。目前，我得到了两项NIH R01赠款，VA优异奖和一个联合加利福尼亚的支持 TRDRP Grant。我实验室的结果大大加深了我们对信号的理解调节并为HF和AD提供了新的治疗靶标。通过这些努力，我收到了 AHA在2010年建立了调查员奖，并成为心脏信号的全球领导者转导。在早期，我的研究重点是心脏β-肾上腺素能受体（BAR）的新特征诸如CAMP-PKA级联反应在心脏收缩功能中的时空调节。过去 10年，我扩展了我的研究计划，以了解疾病的监管信号网络在慢性疾病（例如感染和代谢疾病）下发育。亮点之一是我们已经描述了一种胰岛素受体（INSR）和B2AR的膜蛋白复合不同的组织。 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，痛苦，情绪和中枢神经系统的压力。这些受体信号通路的失调已与 HF和AD的开发。我们最近的研究为理解心血管开辟了一条令人兴奋的途径并发症和神经退行性疾病与糖尿病和代谢综合征有关。一些下面的活跃项目得到了NIH和VA的持续资金支持。当前的VA功绩赠款旨在表征两个蛋白质GRK5和SAP97在肾上腺素的还原（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。我们将找到该法规的发展心脏病的错误，因此提供了治疗心脏病的新颖策略。