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.

项目总结/摘要 酒精性（ALD）和非酒精性脂肪性（NAFLD）肝病是肝病的两种主要病因， 占肝脏相关死亡率的50%以上，并且两者的发病率都在迅速上升。ALD和NAFLD 在组织学上是无法区分的，但在临床上根据不同的酒精阈值进行分层，然而，酒精使用和 代谢风险通常在个体中共存。尽管这些风险经常交叉， 酒精使用和代谢风险随时间推移对肝病进展的影响尚未得到充分研究。一种改进 了解这些相互作用，特别是在不同的个人概况（即年龄，性别，种族）之间，可以 为纤维化评估和监测提供个性化算法， 酒精使用干预。新型生物标志物的研究（例如前蛋白转化酶枯草杆菌蛋白酶Kexin 9型 [PCSK 9]）可能导致预防和治疗肝病的精确干预。为了解决这些知识 差距，我们将利用CARDIA（一个大型的birthday队列，具有35年的前瞻性酒精和代谢 数据）通过对先前储存的血清样品进行系列增强的肝纤维化（ELF）测试来扩增。的 科学目标是：（i）确定酒精使用和肥胖的轨迹和阈值， 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，以确定 根据人口统计学、代谢和酒精特征，肝病风险最高的个体（目标1a）;（iii）评估 通过人口统计学、代谢和酒精特征研究PCSK 9无效等位基因对肝纤维化的作用（目的2）。的 培训目标，将通过正式课程、讲习班、教学法、实践经验和 结构化的指导，是：（一）发展代谢风险和与酒精的相互关系的专业知识;（二） 学习先进的生物统计方法，在多层次的相互作用和纵向分析（如轨迹和 JoinPoint）;（iii）获得翻译生物标志物和遗传流行病学方面的知识，重点是临床 干预措施。这些科学目标和培训目标是由一个丰富的科学环境， 南加州大学，进入一个独特的前瞻性社区为基础的队列（CARDIA），和一个 由Terrault博士组成的强大的多学科导师团队（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 Leventhal博士（酒精和成瘾，纵向研究专家）。所有导师都有重要的 经验与K到R-指导，并将确保李博士的成就的里程碑，将导致他的 作为一个独立的调查员。这项研究将为未来NIH R资助的 研究集中在ALD/NAFLD的筛查和诊断的个性化方法上， 交叉点，利用观察（复杂的纵向生物统计学）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ALD中抗PCSK 9的试点临床试验。