Aspirin and Novel Lipid Mediators in Nonalcoholic Fatty Liver Disease

阿司匹林和新型脂质介质治疗非酒精性脂肪肝

• 批准号: 10478864
• 负责人: Tracey Simon
• 金额: $ 19.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478864
• 关键词: Accounting; Address; Adipose tissue; Adult; Affect; American; Anti-Inflammatory Agents; Area; Aspirin; Attenuated; Biological Markers; Biology; Biopsy; Blinded; Blood; Cessation of life; Chemoprevention; Chronic; Cirrhosis; Clinic; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Conduct Clinical Trials; Data; Databases; Development Plans; Diagnosis; Diagnostic; Dose; Early Diagnosis; Eicosanoids; Endoplasmic Reticulum; Enrollment; Environment; Epidemic; FDA approved; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Foundations; Future; Gastroenterology; Gastrointestinal Hemorrhage; General Hospitals; Goals; Hepatic; Hepatology; Histology; Hospitalization; Human; Individual; Inflammation; Inflammatory; Institutes; Intervention Trial; Knowledge; Lead; Link; Lipids; Liquid Chromatography; Liver; Liver Fibrosis; Liver diseases; Lobular; Magnetic Resonance Spectroscopy; Massachusetts; Measures; Mediator of activation protein; Mentorship; Methods; Morbidity - disease rate; Natural History; Outcome; PTGS2 gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacoepidemiology; Physicians; Placebos; Population; Prevalence; Prevention; Primary carcinoma of the liver cells; Production; Prospective cohort; Protons; Public Health Schools; Randomized Controlled Trials; Research; Research Personnel; Research Priority; Resolution; Risk; Scientist; Serum; Specimen; Steatohepatitis; Sweden; Testing; Time; Training; Work; aged; base; biomarker development; biomarker discovery; career; career development; clinical care; cohort; cyclooxygenase 2; data archive; design; diagnostic biomarker; dosage; effective intervention; effective therapy; experience; falls; follow-up; high dimensionality; improved; improved outcome; in vivo; inhibitor; insight; lipid mediator; lipidomics; liver biopsy; mortality; multidisciplinary; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; noninvasive diagnosis; novel; novel marker; novel therapeutics; patient oriented; pre-clinical; preclinical study; prevent; primary outcome; programs; prospective; randomized placebo controlled trial; risk stratification; secondary endpoint; simple steatosis; skills; skills training; tandem mass spectrometry; targeted biomarker; targeted treatment; tool

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.

项目摘要 候选人特蕾西·西蒙博士是马萨诸塞州将军医院一位颇有成就的临床研究员 医院，接受过胃肠病学和肝病学培训。她的长期职业目标是成为一名 独立的医生调查员，以患者为导向的临床研究计划，致力于非酒精性 脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）。为了实现这一目标，她制定了一个详细的， 综合职业发展计划，旨在提供重点培训，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的经验; 2）获得 代谢脂质组学数据的分析，用于生物标志物的开发; 3）建立在进行临床试验的熟练程度， 试验; 4）获得必要的技能，经验和初步数据，以产生一个成功的R 01应用。 实验和临床数据表明，未解决的炎症是NASH的关键标志，侵袭性炎症是NASH的重要标志。 和炎症形式的NAFLD。作为这一原理的证明，阿司匹林等抗炎药物已经被证明是 以在体内解决NASH并减弱纤维化。这一益处以前归因于抑制促甲状腺激素的产生。 炎症性类二十烷酸脂质合成。然而，最近发现阿司匹林也能刺激 新型抗炎类二十烷酸脂质介质的产生，称为特化促消退介质 （SPM）。基于临床前研究和候选人的初步数据，我们假设NASH反映了 一种相对SPM缺乏的状态，阿司匹林可以通过以下方式解决NASH并改善肝脏结局： 由SPM控制的路径。在目标1中，我们将使用瑞典全国范围内的登记来定义阿司匹林的影响 在经活检证实的NAFLD患者中，用于HCC事件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库存血清和肝脏病理学数据，测量约65个经验证的样本组 靶向SPM，使用最先进的液相色谱串联质谱（LC-MS-MS）平台， 我们将定义并验证NASH的诊断SPM签名。在目标3中，我们将进行试点 随机对照试验，以评估低剂量阿司匹林对NASH消退的初步疗效。西蒙博士 由肝病学著名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，类花生酸生物学，生物标志物发现和NAFLD临床试验，以指导她的道路， 科学独立。她将在MGH脂肪肝诊所出色的科学环境中接受培训， 哈佛公共卫生学院和卡罗林斯卡医学院。完成这个项目将为她提供 对NASH患者进行未来生物标志物指导的阿司匹林干预试验的初步数据。与此 基金会成立后，西蒙博士将利用先进的脂质组学和 药物流行病学工具，以改善NASH的早期检测、风险分层和治疗策略。