Adenosine deaminase 2 regulates macrophage phenotype and liver fibrosis in nonalcoholic fatty liver disease

腺苷脱氨酶2调节非酒精性脂肪肝中的巨噬细胞表型和肝纤维化

• 批准号: 10224178
• 负责人: Zhenghui Gordon Jiang
• 金额: $ 16.74万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224178
• 关键词: Adenosine; Adenosine Triphosphate; Adult; Area; Award; Biological Markers; Biopsy Specimen; Blood; Cardiovascular Diseases; Catabolism; Cells; Cirrhosis; Clinic; Clinical; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Exhibits; Extracellular Space; Fibrosis; Foundations; Funding; Gastroenterology; Goals; Hepatic; Histologic; Human; Immune; Immunohistochemistry; In Situ; In Vitro; Individual; Inflammation; Inflammatory; Inosine; Insulin Resistance; Israel; Knowledge; Kupffer Cells; Lead; Liver; Liver Fibrosis; Malignant neoplasm of liver; Measurement; Measures; Medical center; Medicine; Mentors; Multi-Ethnic Study of Atherosclerosis; Mutation; National Heart, Lung, and Blood Institute; Natural History; Nutrient; Pathologic; Pathway interactions; Patients; Phenotype; Physicians; Plasma; Portal triad; Predictive Value; Primary carcinoma of the liver cells; Principal Investigator; Production; Prospective Studies; Proteins; Public Health Schools; Purines; Recombinants; Research; Research Support; Role; Running; Sampling; Scientist; Steatohepatitis; Stroke; Testing; Therapeutic; Time; Translational Research; Vasculitis; Virulence Factors; Work; adenosine deaminase; career; chronic liver disease; clinical database; extracellular; fibrogenesis; immunoregulation; inflammatory marker; insight; instructor; liver biopsy; liver inflammation; loss of function; macrophage; medical schools; medical specialties; monocyte; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel diagnostics; novel therapeutic intervention; oxidation; paracrine; personalized therapeutic

PROJECT SUMMARY/ABSTRACT Dr. Zhenghui Gordon Jiang, a physician in Gastroenterology at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor in Medicine at Harvard Medical School, has a career goal to establish himself as an independent physician-scientist in the field of nonalcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and liver fibrosis. In addition to running a NAFLD specialty clinic, Dr. Jiang currently spends 70% of his time in translational research supported by the Department of Medicine at BIDMC and external funding such as the CTRA award from the Liver Research Foundation. A K08 award will further provide the protected time and support necessary for him to accomplish the following goals in NAFLD research: 1) define the mechanism by which adenosine deaminase 2 (ADA2) modulates macrophage (MØ) phenotype; 2) establish the impact of ADA2 on inflammation and fibrosis, and 3) test the associations of circulating ADA2 activity with insulin resistance, inflammation and liver fibrosis in NAFLD. Drs. Simon Robson and Kenneth Mukamal are complementary mentors on mechanistic and translational aspects of this project. Dr. Jiang has also identified a panel of advisors and assembled a group of collaborators. Drs. Barbara Wegiel and Yury Popov at BIDMC will provide guidance on MØ and fibrosis research respectively. Dr. Majken Jensen at Harvard Chan School of Public Health will advise on the use of large clinical database and stored samples from the Multi-Ethnic Study of Atherosclerosis (MESA). A proportion of NAFLD patients will develop inflammation and progressive fibrosis ultimately leading to cirrhosis and liver cancer. The mechanism behind this difference in the natural history of NAFLD patients is unclear. Recent work has suggested that the activity of ADA2 in the blood, an ecto-enzyme that catalyzes the conversion of adenosine to inosine, correlate with the histological stage of liver fibrosis in NAFLD patients. Furthermore, MØ in the portal area express ADA2 and accumulate in the setting of steatohepatitis and fibrosis. Our preliminary studies point to the involvement of a novel ADA2 and adenosinergic pathway in regulating inflammation and fibrosis in NAFLD. The central hypothesis is that ADA2 modulates MØ phenotype and influences liver fibrosis in NAFLD. Dr. Jiang further postulates that ADA2 released by infiltrative MØ activates other immune cells in the liver, including Kupffer cells, and perpetuates liver fibrosis and hepatic insulin resistance. The hypothesis will be tested by pursuing two specific aims: Aim 1. To define the ADA2 pathway in modulating MØ by elucidating the immune phenotype associated with ADA2 production, and the mechanism and impact of ADA2 action in vitro and in NAFLD. Aim 2. To define the relationship of circulating ADA2 activity with inflammation, insulin resistance and liver fibrosis among individuals with NAFLD in the Multi-Ethnic Study of Atherosclerosis. The proposed studies will build upon emerging data to further define the ADA2/adenosinergic pathways relevant to liver inflammation and fibrosis in NAFLD, to develop Dr. Jiang's career toward an independent physician- scientist, and to generate the necessary preliminary data to obtain R01-funding at the end of this award.

项目摘要/摘要 贝丝以色列女执事医疗中心(BIDMC)消化内科医生江正辉博士 作为哈佛医学院的一名医学讲师，他的职业目标是将自己确立为 非酒精性脂肪性肝病(NAFLD)、脂肪性肝炎(NASH)领域的独立内科医生兼科学家， 和肝纤维化。除了经营一家NAFLD专科诊所，江医生目前70%的时间都花在 BIDMC医学部支持的转化研究和外部资助，如 肝脏研究基金会颁发的CTRA奖。K08奖励将进一步提供受保护的时间和 他在NAFLD研究中实现以下目标所需的支持：1)通过以下方式确定机制 哪种腺苷脱氨酶2(ADA2)调节巨噬细胞(M？)表型；2)建立ADA2的影响 3)检测循环ADA2活性与胰岛素抵抗的关系， 非酒精性脂肪肝的炎症和肝纤维化。西蒙·罗布森博士和肯尼斯·穆卡马尔博士是互补的 这个项目的机械和翻译方面的导师。江博士还确定了一个顾问小组 并召集了一群合作者。BIDMC的Barbara Wegiel博士和Yury Popov博士将提供指导 分别介绍了M？和纤维化研究。哈佛大学陈公共卫生学院的Majken Jensen博士将建议 关于使用来自动脉粥样硬化多种族研究(MESA)的大型临床数据库和存储样本。 部分非酒精性脂肪肝患者会发展为炎症和进行性纤维化，最终导致肝硬化。 和肝癌。NAFLD患者自然病史的这种差异背后的机制尚不清楚。 最近的研究表明，血液中ADA2的活性，一种催化转化的胞外酶 腺苷与肌苷的比值与NAFLD患者肝纤维化的组织学分期相关。此外，M？ 在汇管区表达ADA2，并在脂肪性肝炎和纤维化的背景下积聚。我们的预赛 研究指出，一种新的ADA2和腺苷能途径参与调节炎症和 非酒精性脂肪肝的纤维化。中心假说是ADA2调节M？表型并影响肝纤维化 在NAFLD。江博士进一步推测，浸润性M？释放的ADA2能激活其他免疫细胞 肝脏，包括枯否细胞，并使肝纤维化和肝脏胰岛素抵抗永久化。假设将是 目的1.通过阐明ADA2信号转导途径，明确ADA2信号转导途径对M？的调节作用 与ADA2产生相关的免疫表型及其在体外作用的机制和影响 在NAFLD。目的2.明确循环ADA2活性与炎症、胰岛素抵抗的关系 在动脉粥样硬化的多种族研究中，非酒精性脂肪肝患者的肝纤维化。 拟议的研究将建立在新兴数据的基础上，以进一步定义相关的ADA2/腺苷能途径 对于NAFLD的肝脏炎症和纤维化，为了将江医生的职业生涯发展成为一名独立的医生- 并生成必要的初步数据，以便在本奖项结束时获得R01--资金。