BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 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
• 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' 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

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 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 新范例，并确定药物筛选和临床治疗的新靶标。我们应用综合 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 在疾病发展中的作用。在过去的 16 年里，我不断获得来自 NIH、VA 和 私人机构。我目前获得两项 NIH R01 资助、一项 VA 优异奖和一项加州联合资助 TRDRP 补助金。我的实验室的结果极大地加深了我们对信号传导的理解 调节并为 HF 和 AD 提供新的治疗靶点。通过这些努力，我获得了 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。过去的事 十年来，我扩大了我的研究项目，以了解疾病中的调节信号网络 在炎症和代谢紊乱等慢性条件下发育。亮点之一是 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 不同的组织。 b2AR 和 InsR 的激活是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 和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 与糖尿病和代谢综合征相关的并发症和神经退行性疾病。一些 以下正在进行的项目得到 NIH 和 VA 持续资助的支持。目前的退伍军人事务部奖学金旨在 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以增强心输出量。我们将了解该法规的实施情况 错误的心脏病，从而提供了治疗心脏病的新策略。