BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618283
• 负责人: HIDEKAZU TSUKAMOTO
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618283
• 关键词: 3' Untranslated Regions; Ablation; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Animals; Attenuated; Award; Binding; California; Caspase; Cell Death; Cell Fate Control; Cellular biology; Chronic; Cirrhosis; Citric Acid Cycle; Clinical; Collaborations; Core Grant; Development; Direct Costs; Disease; Environment; Environmental Risk Factor; Enzymes; Epigenetic Process; Ethanol; Event; Faculty; Fibrosis; Funding; Gastroenterology; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Grant; Growth; Healthcare Systems; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Hepatology; Impairment; Individual; Inflammation; Inflammatory; Infusion procedures; International; Investigation; Investments; Knowledge; Kupffer Cells; Laboratories; Link; Lipids; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Liver neoplasms; Los Angeles; Macrophage; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Medical Research; Mentors; Messenger RNA; Metabolic; Methyl-CpG-Binding Protein 2; Mitochondria; Modeling; Molecular; Monounsaturated Fatty Acids; Mus; National Institute on Alcohol Abuse and Alcoholism; Nuclear Import; Outcome; Oxidative Phosphorylation; PPAR gamma; Pancreatic Diseases; Pathogenesis; Pathway interactions; Patients; Peer Review; Philosophy; Play; Post-Translational Regulation; Protein Dephosphorylation; Publications; Publishing; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; R24; Regulation; Repression; Research; Research Personnel; Respiration; Respiratory Chain; Respiratory physiology; Role; Science; Scientist; Services; Site; Stearoyl-CoA Desaturase; Techniques; Time; Transcriptional Activation; Tumor Promotion; United States Department of Veterans Affairs; United States National Institutes of Health; Up-Regulation; Veterans; beta catenin; career; cell type; chronic liver disease; desaturase; epigenetic regulation; gain of function; genetic risk factor; in vivo; liver inflammation; loss of function; member; morphogens; mouse model; neutrophil; new therapeutic target; notch protein; novel; novel therapeutic intervention; overexpression; problem drinker; programs; pyruvate dehydrogenase; receptor; screening; stem-like cell; therapeutic target; tumor initiation; tumor microenvironment; tumor progression

Dr. Hidekazu (Hide) Tsukamoto continues to make significant contributions to the Medical Research Program of the Department of Veterans Affairs at two distinct levels: first as a Research Physiologist who makes cutting-edge discoveries on molecular cellular mechanisms of liver fibrosis and cancer; and secondly as a Center Director of the P50 national center program on alcoholic liver and pancreatic diseases (ALPD) and cirrhosis who renders concrete and outcome-oriented support for scientific endeavors of VA investigators regionally and across the nation. He published 71 peer-review articles in the last 10 years and maintained federal grants with total current direct costs exceeding $1.1M per year (not inclusive of all center components). He has made major contributions to new knowledge concerning morphogen-mediated regulation of cell fate of hepatic stellate cells (HSCs), hepatic macrophages, and tumor-initiating stem-like cells (TICs), the cell types shown to play critical roles in liver fibrosis, inflammation, and cancer, respectively. In these regulations, novel modes of metabolic reprogramming were disclosed as underlying mechanisms. More specifically, Notch-mediated proinflammatory M1 activation of liver macrophages is causally linked to mitochondrial metabolic reprogramming (J Clin Invest 2015;125:1579-90). Wnt-induced activation of HSCs is mediated by lipid metabolic reprogramming involving stearoyl CoA desaturase (SCD) (Gastroenterology 2017;152:1477-91). Further, SCD expressed by HSCs is shown to achieve tumor-promoting lipid reprogramming in microenvironment to enhance liver tumor progression. Programmatically, he continues to direct a nationally renowned P50 center program on alcoholic liver and pancreatic diseases and a R24 core program on integrative liver cell techniques which support leading-edge ALPD research. Through these programs, he collaborated and supported 12 VA investigators and mentored 10 junior faculty members during the current cycle of the VARCS award. In essence, the efforts Dr. Tsukamoto makes, render individual and collective impacts on science pursed by him and many VA investigators across the nation and help identify therapeutic targets for ALPD and cirrhosis which are prevalent in VA patients.

Hidekazu（Hide）Tsukamoto博士继续为医学做出重大贡献 退伍军人事务部的研究计划在两个不同的层次：第一，作为一个 研究生理学家，在分子细胞机制方面有前沿发现 肝纤维化和癌症;其次是作为P50国家中心的中心主任 酒精性肝脏和胰腺疾病（ALPD）和肝硬化的计划， 和以结果为导向的支持VA研究人员的科学努力区域和跨 归国 在过去的10年里，他发表了71篇同行评议文章，并获得了联邦赠款。 目前每年的直接成本总额超过110万美元（不包括所有中心组成部分）。他 对形态发生素介导的细胞凋亡调控的新知识做出了重大贡献。 肝星状细胞（HSC）、肝巨噬细胞和肿瘤起始干细胞样细胞的细胞命运 细胞（TIC），显示在肝纤维化，炎症和癌症中起关键作用的细胞类型， 分别在这些规定中，代谢重编程的新模式被公开为 基本机制。更具体地说，Notch介导的促炎性M1激活 肝巨噬细胞与线粒体代谢重编程有因果关系（J Clin Invest 2015;125：1579-90）。Wnt诱导的HSC活化由脂质代谢介导 涉及硬脂酰CoA去饱和酶（SCD）的重编程（Gastroenterology 2017;152：1477-91）。 此外，由HSC表达的SCD显示出在肿瘤细胞中实现肿瘤促进脂质重编程。 微环境，以促进肝脏肿瘤的进展。 在项目上，他继续指导全国知名的P50中心项目， 酒精性肝病和胰腺疾病以及R24核心项目整合肝细胞 支持前沿ALPD研究的技术。通过这些项目，他 合作并支持12名VA调查员，并在此期间指导了10名初级教员。 目前的VARCS奖项周期。 从本质上讲，冢本博士的努力，使个人和集体的影响， 他和全国各地的许多退伍军人事务部调查人员所追求的科学， ALPD和肝硬化的治疗靶点，这在VA患者中很常见。