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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要候选人特雷西·西蒙 (Tracey Simon) 博士是马萨诸塞州综合医院 (Massachusetts General) 一位卓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医生。独立的医师研究员，拥有以患者为导向的非酒精性临床研究项目为了实现这一目标，她制定了详细且详细的指南。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的经验；2) 获得以下方面的技能：分析代谢脂质组学数据，用于生物标志物开发；3) 提高临床实施的熟练程度试验；4) 获得成功的 R01 申请所需的技能、经验和初步数据。实验和临床数据表明，未解决的炎症是 NASH 的一个关键标志，NASH 是一种侵袭性的疾病。作为这一原理的证明，阿司匹林等抗炎药物已被证明。在体内解决 NASH 并减轻纤维化的效果先前被归因于抑制 pro- 然而，最近发现阿司匹林也能刺激炎症类二十烷酸脂质的合成。生产新型抗炎类二十烷酸脂质介质，称为专门的促消退介质（SPM）。根据临床前研究和候选者的初步数据，我们努力认为 NASH 反映了这一点。相对 SPM 缺乏的状态，阿司匹林可以通过以下方式解决 NASH 并改善肝脏结果在目标 1 中，我们将使用瑞典全国登记册来定义阿司匹林的影响。在目标 2 中，我们将在活检证实的 NAFLD 患者中使用 HCC 和肝脏相关死亡的风险。使用来自两个独立队列的库存血清和肝脏病理学数据来测量经过验证的约 65 组样本目标 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。 Simon 博士进行了一项随机对照试验，旨在评估低剂量阿司匹林对 NASH 消退的初步疗效。得到由肝病学领域著名科学家和顾问组成的多学科指导团队的支持，药物流行病学、类二十烷酸生物学、生物标志物发现和 NAFLD 临床试验，指导她走向她将在 MGH 脂肪肝诊所出色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学院的完成将为她提供帮助。未来针对 NASH 患者的生物标志物引导的阿司匹林介入试验的初步数据。基金会，西蒙博士将利用先进的脂质组学和药物流行病学工具可改善 NASH 的早期检测、风险分层和治疗策略。