Aspirin and Novel Lipid Mediators in Nonalcoholic Fatty Liver Disease

项目摘要 候选人特蕾西·西蒙博士是马萨诸塞州总医院的一位成就卓著的临床研究员 医院，接受胃肠病和肝病方面的培训。她的长期职业目标是成为一名 独立的医生-调查员，以患者为中心的临床研究计划致力于非酒精患者 脂肪肝(NAFLD)和脂肪性肝炎(NASH)。为了实现这一目标，她制定了一套详细的 综合职业发展计划，旨在提供有针对性的培训，以实现她的短期职业生涯 目标：1)获得药物流行病学和大型数据库研究方面的经验；2)获得药物流行病学和大型数据库研究方面的技能 分析代谢脂组学数据，用于生物标记物的开发；3)熟练地进行临床操作 试验；4)获得必要的技能、经验和初步数据，以产生成功的R01申请。 实验和临床数据表明，未解决的炎症是NASH的一个关键特征，NASH是侵袭性的 炎症型非酒精性脂肪肝。作为这一原理的证据，阿司匹林等抗炎药物已被证明 体内可消解NASH，减轻纤维化。这一益处以前被归因于抑制促肾上腺皮质激素原-2 炎症性二十烷基类脂类合成。然而，最近发现阿司匹林也能刺激 新型抗炎二十烷基类脂类介体的生产，称为专业前驱体介体 (SPM)。根据临床前研究和候选人的初步数据，我们假设纳什反映了 一种相对缺乏SPM的状态，阿司匹林可能通过以下途径缓解NASH并改善肝功能 由SPM管理的通路。在目标1中，我们将使用全国性的瑞典登记来定义阿司匹林的影响 在活检证实的非酒精性脂肪肝患者中，用于发生肝细胞癌和肝脏相关死亡的风险。在目标2中，我们将 使用来自两个独立队列的银行血清和肝脏病理数据来衡量~65人的验证小组 靶向SPMS，使用最先进的LC-MS-MS(LC-MS-MS)平台， 我们将为NASH定义和验证诊断SPM签名。在目标3中，我们将进行一项试点 评价小剂量阿司匹林对Nash消退的初步疗效的随机对照试验。西蒙博士 由著名的肝病科学家和顾问组成的多学科导师团队提供支持， 药物流行病学、二十烷类生物学、生物标记物发现和NAFLD临床试验，以指导她的道路 科学上的独立。她将在MGH脂肪肝诊所卓越的科学环境中接受训练， 哈佛大学公共卫生学院和卡罗林斯卡研究所。完成这个项目将为她提供 用于NASH患者的未来生物标记物引导的阿司匹林介入试验的初步数据。有了这个 基金会，西蒙博士将开始她的独立临床研究生涯，使用先进的脂质组学和 药物流行病学工具，以改进NASH的早期发现、风险分层和治疗策略。

PROJECT ABSTRACT The candidate, Dr. Tracey Simon, is an accomplished clinical research fellow at the Massachusetts General Hospital, with training in gastroenterology and hepatology. Her long-term career goal is to become an independent physician-investigator, with a patient-oriented clinical research program devoted to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). To achieve this, she has developed a detailed and integrated career development plan, designed to provide focused training to achieve her short-term career goals: 1) to gain experience in pharmacoepidemiology and large database research; 2) to acquire skills in the analysis of metabololipidomics data, for biomarker development; 3) to build proficiency in the conduct of clinical trials; 4) to obtain the necessary skills, experience and preliminary data to produce a successful R01 application. Experimental and clinical data show that unresolved inflammation is a key hallmark of NASH, the aggressive and inflammatory form of NAFLD. As proof of this principle, anti-inflammatory drugs like aspirin have been shown in vivo to resolve NASH and attenuate fibrosis. This benefit was previously attributed to the inhibition of pro- inflammatory eicosanoid lipid synthesis. However, it was recently discovered that aspirin also stimulates the production of novel anti-inflammatory eicosanoid lipid mediators, called specialized proresolving mediators (SPMs). Based on preclinical studies and the candidate’s preliminary data, we hypothesize that NASH reflects a state of relative SPM deficiency, and that aspirin may resolve NASH and improve hepatic outcomes through pathways governed by SPMs. In Aim 1, we will use nationwide Swedish registers to define the impact of aspirin use on risk for incident HCC and liver-related death, in patients with biopsy-proven NAFLD. In Aim 2, we will use banked serum and liver pathology data from two independent cohorts, to measure a validated panel of ~65 targeted SPMs, using a state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS-MS) platform, and we will define and validate a diagnostic SPM signature for NASH. In Aim 3, we will conduct a pilot randomized controlled trial to assess the preliminary efficacy of low-dose aspirin on NASH regression. Dr. Simon is supported by a multidisciplinary mentorship team of renowned scientists and advisors in Hepatology, pharmacoepidemiology, eicosanoid biology, biomarker discovery and NAFLD clinical trials, to guide her path to scientific independence. She will train in the outstanding scientific environment of the MGH Fatty Liver Clinic, the Harvard School of Public Health and the Karolinska Institute. Completing this project will provide her with preliminary data towards a future biomarker-guided aspirin interventional trial, for patients with NASH. With this foundation, Dr. Simon will launch her independent clinical research career, using advanced lipidomics and pharmacoepidemiologic tools to improve strategies for early detection, risk stratification and treatment of NASH.