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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要蒋正辉医生，贝斯以色列女执事医疗中心 (BIDMC) 消化内科医师也是哈佛医学院的医学讲师，他的职业目标是将自己打造为一名非酒精性脂肪性肝病 (NAFLD)、脂肪性肝炎 (NASH) 领域的独立医师科学家除了经营NAFLD专科诊所外，江医生目前70%的时间都花在了治疗上。由 BIDMC 医学系和外部资金（例如肝脏研究基金会颁发的 CTRA 奖 K08 奖将进一步提供受保护的时间和时间。他在 NAFLD 研究中实现以下目标所需的支持：1）通过以下方式定义机制：腺苷脱氨酶 2 (ADA2) 调节巨噬细胞 (MØ) 表型 2) 确定 ADA2 的影响；炎症和纤维化，以及 3) 测试循环 ADA2 活性与胰岛素抵抗的关联， NAFLD 中的炎症和肝纤维化是互补的。蒋博士还确定了该项目机械和转化方面的导师。并在 BIDMC 召集了一组合作者 Barbara Wegiel 和 Yury Popov 提供指导。哈佛大学陈公共卫生学院的 Majken Jensen 博士将分别就 MØ 和纤维化研究提供建议。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。一部分 NAFLD 患者会出现炎症和进行性纤维化，最终导致肝硬化 NAFLD 患者自然史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）腺苷到肌苷的变化，与 NAFLD 患者肝纤维化的组织学阶段相关。我们初步认为，汇管区表达 ADA2，并在脂肪性肝炎和纤维化的情况下积累。研究指出新型 ADA2 和腺苷能通路参与调节炎症和 NAFLD 中的纤维化核心假设是 ADA2 调节 MØ 表型并影响肝纤维化。在 NAFLD 中，Jiang 博士进一步假设，浸润性 MØ 释放的 ADA2 激活了 NAFLD 中的其他免疫细胞。肝脏，包括库普弗细胞，并使肝纤维化和肝胰岛素抵抗永久化。测试所追求的两个具体目标：目标 1. 通过阐明调节 MØ 的 ADA2 途径与 ADA2 产生相关的免疫表型，以及 ADA2 体外作用的机制和影响目标 2：确定循环 ADA2 活性与炎症、胰岛素抵抗的关系。动脉粥样硬化多种族研究中 NAFLD 患者的肝纤维化和肝纤维化。拟议的研究将基于新出现的数据，进一步定义相关的 ADA2/腺苷能通路关注NAFLD中的肝脏炎症和纤维化，将姜博士的职业生涯发展为独立医生- 科学家，并生成必要的初步数据，以便在本奖项结束时获得 R01 资助。