Alcohol-associated cholestatic liver injury and mechanisms

酒精相关胆汁淤积性肝损伤及其机制

• 批准号: 10783429
• 负责人: Shengmin Yan
• 金额: $ 14.13万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10783429
• 关键词: ATAC-seq; Academia; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Area; Award; Bile Acids; Biliary; Bioinformatics; Cholestasis; Chronic; Data; Development; Diagnostic; Disease Progression; Dose; Epithelial Cells; Ethanol; Fatigue; Fatty Liver; Functional disorder; Goals; HMGB1 gene; Hepatic; Hepatitis; Hepatocellular Damage; Icterus; Impairment; Inflammation; Inflammatory Response; Injury; Intrahepatic Cholestasis; Knockout Mice; Knowledge; Leukotrienes; Life; Liver; Liver diseases; Mentors; Modeling; Mus; Neutrophil Infiltration; Organoids; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Positioning Attribute; Predisposition; Principal Investigator; Prognosis; Pruritus; Reproducibility; Research; Role; Scientist; Shapes; Testing; Therapeutic; Therapeutic Intervention; Training; Yin; bile formation; career; career development; chronic alcohol ingestion; chronic liver disease; clinical development; expectation; experience; experimental study; fecal transplantation; gut microbiome; gut-liver axis; improved outcome; insight; liver inflammation; liver injury; metabolomics; mouse model; novel; pre-clinical; programs; single-cell RNA sequencing; skills; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics

Project Summary Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease (ALD) with limited therapeutic options. Cholestasis and biliary dysfunction are common in AH patients and can worsen AH prognosis. The central hypothesis is that alcohol consumption reshapes the hepatic microenvironment and predisposes biliary epithelial cells (BECs) to additional injury, causing cholestatic liver injury and contributing to the progression of ALD. The overall objectives for this K01 proposal are to leverage a novel mouse model presenting alcohol-associated cholestasis and hepatitis (AlChoHep) to 1) determine the mechanism by which alcohol consumption predisposes livers to cholestatic liver injury, and 2) elucidate the role of cholestasis in the development of AH. The overall objectives of this application will be attained by pursuing two specific aims: (1) determine the mechanism of cholestasis in ALD and (2) elucidate the role of cholestasis in AH. Under the first aim, the working hypothesis will be determined by fecal microbiome transplant, bile acid depletion, liver organoid cultures, RNA sequencing, and ATAC-seq. Alteration of gut-modified bile acids and gut microbiome will be analyzed. The role of HMGB1 will be studied in liver-specific Hmgb1-knockout mice. The working hypothesis of the second aim will be tested by scFFPE-seq, spatial transcriptomics, metabolomics, leukotriene pathway inhibition, and liver organoid cultures. Upon successful completion of the proposed research, the expectation is to have defined the roles of the gut-liver axis and hepatocellular HMGB1 in the development of alcohol-associated cholestasis (Aim 1), and to have elucidated the impact of cholestasis on the liver microenvironment and how this contributes to the pathogenesis of AH (Aim 2). This K01 application will promote the development of the applicant into a multidisciplinarily trained independent principal investigator. The applicant has assembled a Mentoring Committee composed of outstanding scientists, including three mentors (Drs. Xiao-Ming Yin, Wenke Feng, and Xiaojiang Xu) and two key collaborators (Drs. Jay Kolls and Suthat Liangpunsakul), who are renowned hepatologists or well-recognized scientists in the field of ALD, gut-liver axis, inflammation, and bioinformatics, with an outstanding record of training junior scientists to be independent and successful in academia. They will direct the applicant’s career development and provide full support to the implementation of the proposed experiments. Upon completion of the studies, the applicant will receive additional training from the Mentoring Committee to gain expertise in several areas, including gut-liver axis, the pathophysiology of AH, liver inflammation, and bioinformatics. The successful completion of the proposed project will yield significant data for a follow-on R01 level application.

项目摘要 酒精相关性肝炎（AH）是一种严重的、可能危及生命的酒精相关性肝病 疾病（ALD），治疗选择有限。胆汁淤积和胆道功能障碍在AH中常见 患者，并可能恶化AH预后。核心假设是酒精消费重塑了 肝脏微环境的变化，使胆管上皮细胞（BEC）易受额外损伤， 胆汁淤积性肝损伤，并促进ALD的进展。本K 01的总体目标 建议是利用一种新的小鼠模型， （AlChoHep）以1）确定酒精消费使肝脏易于发生以下疾病的机制 胆汁淤积性肝损伤，和2）阐明胆汁淤积在AH的发展中的作用。整体 本申请的目的将通过追求两个具体目标来实现：（1）确定机制 （2）阐明胆汁淤积在AH中的作用。在第一个目标下， 通过粪便微生物组移植、胆汁酸消耗、肝类器官培养 RNA测序和ATAC-seq.肠道修饰的胆汁酸和肠道微生物组的改变将是 分析了HMGB 1的作用将在肝脏特异性Hmgb 1基因敲除小鼠中进行研究。工作 第二个目的的假设将通过scFFPE-seq，空间转录组学，代谢组学， 白三烯途径抑制和肝类器官培养。在成功完成拟议的 研究中，期望能够确定肠-肝轴和肝细胞HMGB 1在 酒精相关性胆汁淤积的发展（目标1），并阐明 胆汁淤积对肝脏微环境的影响，以及这如何导致AH的发病机制（目的2）。 此K 01应用程序将促进申请人的发展成为一个多学科培训 独立首席调查员申请人已组建了一个指导委员会， 杰出的科学家，包括三位导师（尹小明博士，冯文科博士和徐晓江博士）， 两位主要合作者（Jay Kolls博士和Suthat Liangpunsakul博士），他们是著名的肝病学家， 在ALD，肠道-肝脏轴，炎症和生物信息学领域的知名科学家， 在培训年轻科学家以使其独立并在学术界取得成功方面有着出色的记录。他们将 指导申请人的职业发展，并提供全面支持，以实施拟议的 实验完成课程后，申请人将接受 指导委员会获得几个领域的专业知识，包括肠-肝轴， 肝脏炎症和生物信息学。成功完成拟议项目将产生 为后续R 01级应用提供重要数据。