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: 9313262
• 负责人: EDWARD A DENNIS
• 金额: $ 68.52万
• 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/9313262
• 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; Histologic; 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; 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; metabolome; model building; mortality; non-alcoholic fatty liver; nonalcoholic steatohepatitis; point of care; point-of-care diagnostics; prospective; public health relevance; 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（由申请人提供）：非酒精性脂肪性肝炎 (NASH) 是非酒精性脂肪性肝病 (NAFLD) 的一种侵袭性形式，影响 3-4% 的成年人口，并在 15-20% 的受影响受试者中进展为肝硬化。目前还没有批准的 NASH 治疗方法，诊断这种疾病的唯一准确方法是肝活检，这种方法是侵入性的、痛苦的，有时会导致死亡。许多人认为，缺乏用于诊断 NASH、评估疾病进展与消退以及对各种治疗方法的反应的“即时护理”诊断工具是大规模识别受影响个体和针对 NASH 药物开发的最重要障碍。该提案代表了多个 PI 的努力，旨在开发基于脂质组学的生物标志物组，以填补这些知识空白。来自 NIDDK NASH 临床研究网络 (CRN) 的 Sanyal 博士 (PI) 将领导这项工作，之前领导 NIGMS LIPID_MAPS 联盟的 Dennis 博士 (Co-PI) 将领导血脂分析。 NASH CRN 数据协调中心（DCC）将继续担任该提案的 DCC。这些研究将取自 NASH CRN 生物储存库，其中包含从 2000 多名患有 NAFLD 的高表型受试者进行肝活检时抽取的血浆。三个具体目标将检验以下假设：NAFLD 中脂质代谢的变化可以识别 NASH 的循环脂质特征诊断、疾病进展和对特定疗法的反应。目标 1 将定义并验证潜在 NASH 及其严重程度的循环血脂诊断。将研究模型构建队列和两个验证队列。模型构建队列将包括患有和不患有 NAFLD 的受试者。验证队列将包括：(1) 一组具有不同 NAFLD 表型的受试者以及无 NAFLD 的年龄、性别、种族和体重匹配对照受试者，以及 (2) 一组处于“真实世界”环境中的前瞻性受试者，他们将接受临床指示的疑似 NASH 肝活检。目标 2 将定义循环脂质的变化来诊断 NASH 疾病进展。这将通过对一组具有不同 NAFLD 表型且接受过两次或多次肝活检的受试者进行基线肝活检时抽取的血浆进行脂质组学分析来实现。目标 3 将定义与治疗引起的 NASH 改善相关的循环脂质特征。这将利用在 NASH CRN 参与临床试验的受试者的方案驱动活检过程中获得的独特样本集。这些研究将通过应用 LIPID_MAPS 开发的最先进的分析平台来进一步创新，用于 NASH 的诊断开发。初步数据支持拟议研究和目标的可行性。这些研究将满足诊断准确性评估 (QUADAS) 的所有质量指标，并将通过开发允许 NASH 即时评估的诊断平台，对该领域产生强烈的积极影响。这将增加获得护理的机会，并最终改善人们的健康，从而与 NIH 的使命保持一致。