LIPIDOMICS BASED DIAGNOSTICS FOR NONALCOHOLIC STEATOHEPATITIS

基于脂质组学的非酒精性脂肪性肝炎诊断

• 批准号: 9132243
• 负责人: EDWARD A DENNIS
• 金额: $ 69.26万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-26 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132243
• 关键词: Acids; Adult; Affect; Age; Area; Bedside Testings; Biopsy; Cause of Death; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Cluster Analysis; Collaborations; Data; Data Coordinating Center; Data Set; Databases; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease Progression; Enrollment; Evaluation; Functional disorder; Funding; Gender; Glues; Goals; Grant; Health; Health Services Accessibility; Individual; Institutes; Knowledge; Lead; Lipids; Liver diseases; Logistic Regressions; Measures; Methods; Mission; Modality; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; Pain; Performance; Phenotype; Pioglitazone; Plasma; Population; Positioning Attribute; Principal Component Analysis; Protocols documentation; Public Health; Race; Receiver Operating Characteristics; Research Personnel; Sampling; Severities; Staging; Testing; Therapeutic; Therapeutic Agents; Time; United States National Institutes of Health; Validation; Vitamin E; Weight; base; biobank; biomarker panel; circulating biomarkers; cohort; data mining; disorder control; drug development; improved; innovation; lipid metabolism; liver biopsy; meetings; metabolome; model building; mortality; non-alcoholic fatty liver; nonalcoholic steatohepatitis; point of care; point-of-care diagnostics; prospective; research clinical testing; response; scale up; statistics; tool; treatment response

 DESCRIPTION (provided by applicant): Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) that affects 3-4% of the adult population and progresses to cirrhosis in 15-20% of affected subjects. There is currently no approved therapy for NASH and the only accurate method to diagnose this condition is a liver biopsy which is invasive, painful and occasionally associated with mortality. The lack of a "point-of-care" diagnostic tool to diagnose NASH, to assess disease progression versus regression and response to various therapeutics is considered by many to be the most important barrier towards large scale identification of affected individuals and for drug-development against NASH. This proposal represents a multi-PI effort to develop a lipidomics-based biomarker panel to fill these gaps in knowledge. Dr. Sanyal (PI) from the NIDDK NASH Clinical Research Network (CRN) will lead this effort and Dr. Dennis (Co-PI) who previously led the NIGMS LIPID_MAPS consortium will lead the lipid analysis. The NASH CRN data coordinating center (DCC) will continue to serve as the DCC for this proposal. The studies will draw from the NASH CRN biorepository which contains plasma drawn at the time of a liver biopsy from over 2000 highly phenotyped subjects with NAFLD. Three specific aims will test the hypothesis that changes in lipid metabolism in NAFLD allow identification of a circulating lipid signature diagnostic of NASH, disease progression and response to specific therapies. Aim 1 will define and validate a circulating lipid profile diagnostic of underlying NASH and its severity. A model building cohort and two validation cohorts will be studied. The model building cohort will include subjects with and without NAFLD. The validation cohort will include: (1) a group of subjects with varying phenotypes of NAFLD and age, gender, race and weight-matched controls without NAFLD, and (2) a prospective group of subjects in a "real-world" setting who are going to receive a clinically-indicated liver biopsy for suspected NASH. Aim 2 will define changes in circulating lipids diagnostic of disease progression in NASH. This will be accomplished by performing lipidomic analyses on plasma drawn at the time of baseline liver biopsies in a cohort of subjects with varying phenotypes of NAFLD who have undergone two or more liver biopsies. Aim 3 will define the circulating lipid signature associated with treatment-induced improvement of NASH. This will utilize unique sample-sets obtained during protocol-driven biopsies from subjects enrolled in clinical trials by the NASH CRN. The studies will further innovate by applying the state-of-the-art analytic platforms developed by LIPID_MAPS for diagnostics development for NASH. Preliminary data support the feasibility of the proposed studies and aims. These studies will meet all of the quality metrics for accuracy assessment of diagnostics (QUADAS) and will have a strong positive impact on the field by allowing development of a diagnostic platform that will permit point of care evaluation of NASH. This will enhance access to care and eventually improve the health of the people thereby aligning with the mission of the NIH.

 描述（由适用提供）：非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪肝病（NAFLD）的侵略性形式，影响了3-4％的成人人群，并在15-20％受影响的受试者中发展为cirrhosis。目前尚无针对NASH的批准疗法，诊断此疾病的唯一准确方法是肝活检，具有侵入性，痛苦且有时与死亡率相关。缺乏用于诊断NASH的“护理点”诊断工具，无法评估疾病进展与回归和对各种治疗疗法的反应，这是许多人认为是对受影响个体的大规模识别以及针对NASH进行药物发展的最重要障碍。该提案代表了开发基于脂肪态学的生物标志物小组以填补这些知识中的这些差距的多PIC努力。 NIDDK NASH临床研究网络（CRN）的Sanyal（PI）博士将领导这项工作，而Dennis（Co-Pi）先前领导Nigms Lipid_maps Consortium，将领导脂质分析。 NASH CRN数据协调中心（DCC）将继续作为该建议的DCC。这些研究将从NASH CRN生物座位上汲取灵感，该生物座是在2000多名具有NAFLD的高度表型受试者的肝活检时绘制的血浆。三个具体目的将检验以下假设：NAFLD中脂质代谢的变化允许鉴定NASH，疾病进展和对特定疗法的反应的循环脂质特征诊断。 AIM 1将定义和验证纳什及其严重性的循环脂质剖面诊断。模型构建队列和两个验证队列将进行研究。模型构建队列将包括有和没有NAFLD的主题。验证队列将包括：（1）一组具有NAFLD和年龄，性别，种族和体重匹配的控制的受试者，没有NAFLD，以及（2）在“现实世界中”设置中的一组潜在受试者，这些受试者将接受临床指示的肝脏biopsy涉及可疑NASH。 AIM 2将定义NASH疾病进展诊断的循环脂质的变化。这将通过在基线肝活检中对等离子体进行脂组学分析来实现，其中包括经历了两个或多个活检的NAFLD表型不同的受试者。 AIM 3将定义与治疗引起的NASH改善相关的循环脂质签名。这将利用NASH CRN参加临床试验的受试者的方案驱动的活检中获得的独特样品集。这些研究将通过应用LIPID_MAP开发的最先进的分析平台来进一步创新NASH的诊断开发。初步数据支持拟议的研究和目标的可行性。这些研究将满足所有质量指标的准确评估（Quadas），并通过允许开发诊断平台对现场产生强烈的积极影响，该平台将允许对NASH进行护理点评估。这将增强获得护理的机会，并最终改善人们的健康状况，从而与NIH的任务保持一致。