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

项目总结/摘要 博士Jiang Zhenghui Gordon，贝斯以色列女执事医疗中心（BIDMC）消化科医生 他是哈佛医学院的医学讲师，他的职业目标是成为一名 非酒精性脂肪性肝病（NAFLD）、脂肪性肝炎（NASH）、 和肝纤维化除了经营NAFLD专科诊所外，蒋医生目前70%的时间都花在 由BIDMC医学系和外部资金支持的转化研究，如 肝脏研究基金会的CTRA奖。K 08奖励将进一步提供受保护的时间， 支持他在NAFLD研究中实现以下目标所必需的：1）通过以下方式定义机制： 腺苷脱氨酶2（ADA 2）调节巨噬细胞（MMP 2）表型; 2）确定ADA 2的影响 对炎症和纤维化的影响，以及3）测试循环ADA 2活性与胰岛素抵抗的关联， 炎症和肝纤维化。Simon Robson博士和Kenneth Mukamal博士是互补的 该项目的机械和翻译方面的导师。江博士还指定了一个顾问小组 召集了一群合作者BIDMC的Barbara Wegiel博士和Yury Popov博士将提供指导 分别对心肌梗塞和纤维化进行研究。哈佛陈冯富珍公共卫生学院的马杰肯詹森博士将建议 使用来自多种族动脉粥样硬化研究（梅萨）的大型临床数据库和存储样本。 一部分NAFLD患者会发生炎症和进行性纤维化，最终导致肝硬化。 和肝癌。NAFLD患者自然史中这种差异背后的机制尚不清楚。 最近的研究表明，血液中ADA 2的活性，一种催化转化的胞外酶， 腺苷转化为肌苷与NAFLD患者肝纤维化的组织学分期相关。此外， 在汇管区表达ADA 2并在脂肪性肝炎和纤维化的情况下积累。我们的初步 研究指出，一种新的ADA 2和腺苷能途径参与调节炎症， NAFLD中的纤维化核心假设是ADA 2调节MMP 2表型并影响肝纤维化 在NAFLD。Jiang博士进一步假设，由浸润性MMPs释放的ADA 2激活了细胞中的其他免疫细胞。 肝脏，包括枯否细胞，并使肝纤维化和肝胰岛素抵抗永久化。假设是 通过追求两个具体目标进行测试：目标1。为了通过阐明ADA 2通路在调节MMP 2中的作用， 与ADA 2产生相关的免疫表型，以及ADA 2体外作用的机制和影响 在NAFLD。目标2.明确循环ADA 2活性与炎症、胰岛素抵抗的关系 多种族动脉粥样硬化研究中NAFLD患者的肝纤维化。 拟议的研究将建立在新出现的数据基础上，以进一步确定ADA 2/腺苷能通路相关的 NAFLD的肝脏炎症和纤维化，将姜医生的职业生涯发展为独立的医生- 科学家，并产生必要的初步数据，以获得R 01-资金在本奖项结束。

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.