Estimating the Contribution of Alcohol and Metabolic Risk to Liver Disease Progression to Inform Personalized Interventions

估计酒精和代谢风险对肝病进展的影响，为个性化干预措施提供信息

• 批准号: 10352120
• 负责人: Brian Pei Lim Lee
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352120
• 关键词: Accounting; Achievement; Address; Adult; Age; Alcohol consumption; Alcohols; Algorithms; Alleles; Behavioral; Biological Markers; Biometry; Biostatistical Methods; Black Populations; Black race; Blood specimen; Body Weight decreased; Body mass index; California; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Cholesterol; Clinical; Clinical Research; Clinical Trials; Communities; Complex; Coronary Artery Risk Development in Young Adults Study; Data; Deposition; Devices; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Educational workshop; Ensure; Environment; Epidemic; Etiology; FDA approved; Fatty acid glycerol esters; Fibrosis; Foundational Skills; Funding; Future; Genetic; Genotype; Goals; Health; Healthcare; Heavy Drinking; Hepatic Fibrogenesis; Hepatitis; Histologic; Histology; Human; Hyaluronic Acid; Incidence; Individual; Inflammation; Injury; Intervention; Investigation; Knowledge; Lead; Learning; Liver; Liver Fibrosis; Liver diseases; Longitudinal Studies; Low Prevalence; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Measures; Medical Care Costs; Mentors; Mentorship; Metabolic; Modeling; Monitor; Morbidity - disease rate; Obesity; Other Genetics; Outcome; Participant; Patient-Focused Outcomes; Peptides; Persons; Pharmacology; Population; Positioning Attribute; Procollagen; Proprotein Convertases; Questionnaires; Race; Rattus; Registries; Research; Research Personnel; Risk; Role; Sampling; Serum; Serum Markers; Steatohepatitis; Structure; Subtilisins; Surveys; Testing; Time; Tissues; Training; Underrepresented Minority; United States; United States National Institutes of Health; Universities; Woman; addiction; alcohol effect; base; behavioral outcome; biracial; chronic liver disease; cohort; design; disease diagnosis; effective intervention; end stage liver disease; epidemiology study; experience; follow-up; genetic epidemiology; high risk; improved; inhibitor; interest; lens; liver injury; longitudinal analysis; men; mortality; multidisciplinary; non-alcoholic fatty liver disease; novel; novel marker; personalized approach; personalized intervention; personalized medicine; prevent; prognostic; prognostication; prospective; racial disparity; recruit; screening; sex; sex disparity; statistics; therapeutic target; translational study; trend; young adult

PROJECT SUMMARY/ABSTRACT Alcohol- (ALD) and non-alcoholic fatty (NAFLD) liver disease are the two leading etiologies of liver disease, accounting for more than 50% of liver-related mortality, and both rapidly rising in incidence. ALD and NAFLD are histologically indistinguishable, but clinically stratified by distinct alcohol thresholds—yet, alcohol use and metabolic risk often co-exist in individuals. Despite the frequent intersection of these risks, the longitudinal effects of alcohol use and metabolic risk over time on liver disease progression are understudied. An improved understanding of these interactions, particularly among different individual profiles (i.e. age, sex, race), can inform personalized algorithms for fibrosis assessment and surveillance, and individualized thresholds for alcohol use interventions. Investigation of novel biomarkers (e.g. proprotein convertase subtilisin kexin type 9 [PCSK9]) may lead to precision-interventions to prevent and treat liver disease. To address these knowledge gaps, we will leverage CARDIA (a large biracial cohort with 35 years of prospective alcohol and metabolic data) amplified by serial Enhanced Liver Fibrosis (ELF) testing of previously banked serum samples. The scientific aims are to: (i) identify trajectories and thresholds of alcohol use and obesity, associated with presence and progression of liver fibrosis (Aim 1); (ii) develop sex- and race-specific models to identify individuals at highest risk of liver disease, by demographic, metabolic, and alcohol profiles (Aim 1a); (iii) assess the role of null PCSK9 alleles on liver fibrosis by demographic, metabolic, and alcohol profiles (Aim 2). The training goals, which will be achieved through formal courses, workshops, didactics, hands-on experience and structured mentorship, are to: (i) develop expertise in metabolic risks and inter-relatedness with alcohol; (ii) learn advanced biostatistical methods in multi-level interactions and longitudinal analyses (e.g. trajectory and JoinPoint); (iii) acquire knowledge in translational biomarkers and genetic epidemiology, focused on clinical interventions. These scientific aims and training goals are made possible by a rich scientific environment at University of Southern California, access to a unique prospective community-based cohort (CARDIA), and a strong multidisciplinary mentorship team consisting of Dr. Terrault (chronic liver diseases, clinical and translational studies, clinical trials expert), Dr. Mack (advanced biostatistics, genetic epidemiology, clinical trials expert), and Dr. Leventhal (alcohol and addiction, longitudinal studies expert). All mentors have significant experience with K to R-mentorship, and will ensure Dr. Lee’s achievement in milestones that will lead to his position as a productive independent investigator. This research will set the stage for future NIH R-funded studies focused on personalized approaches to the screening and prognostication within the ALD/NAFLD intersection, leveraging expertise in observational (complex longitudinal biostatistics) and translational (biomarkers, genetic epidemiology) research, in addition to a pilot clinical trial of anti-PCSK9 in ALD.

项目概要/摘要 酒精肝病（ALD）和非酒精性脂肪肝病（NAFLD）是肝病的两个主要病因， 占肝脏相关死亡率的 50% 以上，且 ALD 和 NAFLD 的发病率均迅速上升。 在组织学上无法区分，但在临床上通过不同的酒精阈值进行分层 - 然而，饮酒和饮酒 代谢风险通常在个体中共存，尽管这些风险经常交叉存在，但纵向来看。 随着时间的推移，饮酒和代谢风险对肝病进展的影响尚未得到充分研究。 了解这些相互作用，特别是不同个人资料（即年龄、性别、种族）之间的相互作用，可以 为纤维化评估和监测的个性化算法以及个体化阈值提供信息 酒精使用干预措施的研究（例如前蛋白转化酶枯草杆菌蛋白酶 9 型） [PCSK9]）可能会导致预防和治疗肝病的精确干预措施来解决这些知识。 差距，我们将利用 CARDIA（一个大型混血儿队列，拥有 35 年的前瞻性酒精和代谢研究 数据）通过对先前储存的血清样本进行连续增强肝纤维化（ELF）测试而放大。 科学目标是：(i) 确定与酒精使用和肥胖相关的轨迹和阈值 肝纤维化的存在和进展（目标 1）；(ii) 开发性别和种族特异性模型来识别 根据人口统计、代谢和酒精状况，患有肝病风险最高的个体（目标 1a）； 通过人口统计学、代谢和酒精谱分析 PCSK9 无效等位基因对肝纤维化的作用（目标 2）。 培训目标，将通过正式课程、讲习班、教学、实践经验和 结构化指导的目的是：(i) 发展代谢风险和与酒精的相互关系方面的专业知识；(ii) 学习多层次相互作用和纵向分析中的先进生物统计方法（例如轨迹和 JoinPoint）；（iii）获得转化生物标志物和遗传流行病学方面的知识，重点是临床 这些科学目的和培训目标是通过丰富的科学环境实现的。 南加州大学，获得独特的前瞻性社区队列 (CARDIA)，以及 由 Terrault 博士（慢性肝病、临床和 转化研究、临床试验专家），Mack 博士（高级生物统计学、遗传流行病学、临床试验 专家）和 Leventhal 博士（酒精和成瘾纵向研究专家）。 拥有从 K 到 R 指导的经验，并将确保李博士取得里程碑式的成就，从而引领他的事业 作为一名富有成效的独立研究者，这项研究将为未来 NIH R 资助奠定基础。 研究重点是 ALD/NAFLD 筛查和预测的个性化方法 交叉点，利用观察（复杂纵向生物统计学）和转化方面的专业知识 （生物标志物、遗传流行病学）研究，以及针对 ALD 的抗 PCSK9 临床试验。