BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10369578
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/10369578
关键词：
ADRBK1 gene Adrenergic Agents Adrenergic Receptor Alzheimer&apos s Disease Amyloid beta-Protein Angiotensins Animal Model Asthma Atrial Fibrillation Award Biosensor Blood Circulation Brain California Cardiac Cardiac Myocytes Cardiac Output Cardiac development Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell physiology Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Clinical Clinical Trials Cognition Collaborations Complex Complications of Diabetes Mellitus 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 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 Pathway Signal Transduction Signaling Molecule Stress Synapses System Therapeutic Therapeutic Intervention Tissues Transgenic Model Translating United States National Institutes of Health Veterans alpha synuclein gene beta-2 Adrenergic Receptors beta-adrenergic receptor biochemical tools cardiogenesis 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

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.

我研究的总体目标是了解慢性病病理生理学的潜在机制我的目标是发现未知的疾病，特别是心力衰竭（HF）和阿尔茨海默病（AD）。新范例，并确定药物筛选和临床治疗的新靶标。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础原理及其功能在过去的 16 年里，我不断获得来自 NIH、VA 和的资助。我目前获得两项 NIH R01 拨款、一项 VA 优异奖和一项加州联合资助的支持。我的实验室的研究结果极大地加深了我们对信号传导的理解。通过这些努力，我获得了新的治疗靶点。 AHA 于 2010 年设立了研究者奖，并将我自己确立为心脏信号传导领域的全球领导者转导。早年，我的研究重点是心脏β-肾上腺素能受体（bAR）的新特征信号传导，例如心脏收缩功能中 cAMP-PKA 级联的时空调节。十年来，我扩展了我的研究计划，以了解疾病中的调节信号网络炎症和代谢紊乱等慢性条件下的发育是亮点之一。我们已经描述了胰岛素受体 (InsR) 和 b2AR 的膜蛋白复合物，广泛表达于 b2AR 和 InsR 的激活是心血管功能的关键调节机制。这些受体还调节认知功能，包括记忆和学习、疼痛、情绪。这些受体信号通路的失调与中枢神经系统的压力有关。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。与糖尿病和代谢综合征相关的并发症和神经退行性疾病。以下正在进行的项目得到了 NIH 和 VA 持续资助的支持。描述两种蛋白质 GRK5 和 SAP97 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来增强心输出量我们将了解这种调节是如何进行的。错误的心脏病，从而提供了治疗心脏病的新策略。