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 Zhenghui Gordon Jiang博士，贝丝以色列执事医疗中心（BIDMC）的胃肠病学物理学 哈佛医学院的医学讲师的职业目标是将自己确立为 非酒精性脂肪肝病（NAFLD），脂肪性肝炎（NASH）， 和肝纤维化。除了经营NAFLD专业诊所外，Jiang博士目前还花了70％的时间 BIDMC医学部支持的翻译研究和外部资金，例如 肝脏研究基金会的CTRA奖。 K08奖项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必需的支持：1）通过 腺苷脱氨酶2（ADA2）调节巨噬细胞（Mø）表型； 2）建立ADA2的影响 关于炎症和纤维化，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。博士。西蒙·罗布森（Simon Robson）和肯尼思·穆卡马尔（Kenneth Mukamal） 指导该项目的机理和翻译方面。江博士还确定了顾问小组 并组建了一组合作者。博士。 BIDMC的Barbara Wegiel和Yury Popov将提供指导 在Mø和纤维化研究上。哈佛大学公共卫生学院的Majken Jensen博士将建议 关于使用大型临床数据库并存储了来自动脉粥样硬化多种族研究（MESA）的样品。 一部分NAFLD患者将发展影响和进行性纤维化，最终导致肝硬化 和肝癌。 NAFLD患者自然史的这种差异背后的机制尚不清楚。 最近的工作表明，ADA2在血液中的活性是一种催化转化率的酶 - 酶 腺苷至肌苷，与NAFLD患者的肝纤维化组织学阶段相关。此外，莫 在门户区域，表达ADA2并在脂肪性肝炎和纤维化的情况下积聚。我们的初步 研究指出，新型ADA2和腺苷能途径参与调节注射和 NAFLD中的纤维化。中心假设是ADA2调节MøChtype并影响肝纤维化 在Nafld。 Jiang博士进一步假设，浸润Mø释放的ADA2激活了其他免疫细胞 肝脏，包括kupffer细胞，并使肝纤维化和肝胰岛素抵抗永久化。假设将是 通过追求两个具体目标测试：目标1。通过阐明Mø来定义ADA2途径 与ADA2产生相关的免疫表型以及ADA2作用在体外的机制和影响 和nafld。目标2。定义循环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，NAFLD患者之间的肝纤维化。 拟议的研究将基于新兴数据，以进一步定义ADA2/腺苷能途径相关 NAFLD中的肝脏炎症和纤维化，以发展江尔德博士的职业生涯 科学家，并生成必要的初步数据以在本奖项结束时获得R01资助。