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

基本信息

批准号：
10666352
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
项目类别：
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/10666352
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 Breakthrough device California Cardiovascular Diseases Cardiovascular system Caring Categories Cessation of life Characteristics Cholesterol Clinical Clinical Research Clinical Trials Clinical stratification Communities Complex Coronary Artery Risk Development in Young Adults Study Data Deposition Diabetes Mellitus Diagnosis Disease Disease Progression Educational workshop Ensure Environment Epidemic Etiology FDA approved Fatty acid glycerol esters Fibrosis Foundational Skills Funding Future Genetic Genetic Carriers Genetic Markers Genotype Goals Guidelines Health Heavy Drinking Hepatic Fibrogenesis Hepatitis Histologic Histology Human Hyaluronic Acid Incidence Individual Inflammation Injury Intervention Investigation Knowledge Knowledge acquisition 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 Population Positioning Attribute Procollagen Productivity Proprotein Convertases Questionnaires Race Rattus Recommendation 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 biomarker validation biracial chronic liver disease cohort design disease diagnosis effective intervention end stage liver disease 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 pharmacologic prevent prognostic prognostication prospective racial disparity recruit screening sex sex disparity statistics therapeutic target translational study trend young adult

项目摘要

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.

项目摘要/摘要酒精（ALD）和非酒精脂肪（NAFLD）肝病是肝病的两个主要病因，占与活死亡率相关的50％以上，并且发病率都迅速上升。 Ald和Nafld 在组织学上是无法区分的，但在临床上通过不同的酒精阈值进行了分层 - 代谢风险通常在个体共存。尽管这些风险经常相交，但纵向了解酒精使用和代谢风险随着时间的流逝对肝病进展的影响。改进了解这些互动，特别是在不同的个人概况（即年龄，性别，种族）中，可以为个性化算法提供纤维化评估和监视的信息，以及个性化的阈值酒精使用干预措施。新型生物标志物的研究（例如，促蛋白转化酶枯草蛋白Kexin型9型 [PCSK9]）可能导致预防和治疗肝病的精确干扰。解决这些知识差距，我们将利用Cardia（一个大的混蛋队列，有35年的潜在酒精和代谢数据）通过对先前库的血清样品的串行增强肝纤维化（ELF）测试进行扩增。这科学目的是：（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（AIM 1）；（ii）开发性别和种族特异性模型以识别通过人口统计，代谢和酒精谱的肝病风险最高的个体（AIM 1A）；（iii）评估 NULL PCSK9等位基因通过人口统计学，代谢和酒精特征的作用（AIM 2）。培训目标将通过正规课程，讲习班，教学，动手经验和结构化的精神训练是：（i）在代谢风险和与酒精相关性相关性方面发展专业知识；（ii）在多级相互作用和纵向分析中学习先进的生物统计学方法（例如 JOINPOINT）; （iii）获取转化生物标志物和遗传流行病学的知识，重点是临床干预措施。这些科学目标和培训目标是通过丰富的科学环境使南加州大学，获得独特的前瞻性社区队列（Cardia）和A 强大的多学科心态团队由Terrault博士组成（慢性肝病，临床和翻译研究，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（酒精与成瘾，纵向研究专家）。所有导师都有很大的具有K到R-Commentorship的经验，并将确保Lee博士在里程碑中的成就，这将导致他的作为产品独立研究者的位置。这项研究将为未来的NIH R-资助奠定基础研究重点是个性化筛查和提示在ALD/NAFLD中的方法交叉点，利用观测（复杂纵向生物统计学）和翻译的专业知识（生物标志物，遗传流行病学）研究，除了ALD中的抗PCSK9试验临床试验外。