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Impact of Maternal Obesity on Offspring Non-alcoholic Fatty Liver Disease: Role of Bile Acid Homeostasis and Microbiome

母亲肥胖对后代非酒精性脂肪肝的影响：胆汁酸稳态和微生物组的作用

基本信息

批准号：
10671356
负责人：
Michael D Thompson
金额：
$ 6.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671356
关键词：
16S ribosomal RNA sequencing Adult Affect Antibiotics Basic Science Bile Acids Child Childhood Cholestyramine Cicatrix Cirrhosis Clinical Collagen Consumption Data Deposition Development Development Plans Diet Disease Progression Disease Resistance Doctor of Philosophy Drug Metabolic Detoxication Endocrinology Event Excretory function Exhibits Exposure to Fatty Liver Fatty acid glycerol esters Feces Fibrosis Gastroenterology Gene Expression Generations Goals Health system Hepatic Hepatology High Fat Diet Homeostasis Hydrophobicity Inflammation Inflammatory Insulin Resistance Intestines K-Series Research Career Programs Knowledge Lead Link Liver Liver diseases Mentors Metabolic Metabolism Modeling Modification Molecular Mothers Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathogenicity Patients Perinatal Phenotype Physicians Preventive therapy Principal Investigator Production Progressive Disease Public Health Research Research Design Research Personnel Resources Risk Role Scientist Standard Model Steatohepatitis Testing Time Training Transplantation United States Universities Ursodeoxycholic Acid Vertical Disease Transmission Washington base bile acid metabolism bile duct career development cellular pathology cholesterol absorption clinically relevant design dietary control disorder risk economic impact efficacy evaluation experience experimental study fatty liver disease feeding hydrophilicity in utero liver injury liver transplantation maternal obesity microbiome microbiome research molecular pathology non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel obesogenic offspring prevent programs sugar targeted treatment transcriptomics western diet

项目摘要

PROJECT SUMMARY/ABSTRACT The primary goal of this proposal is to develop the principal investigator, Dr. Michael Thompson, into an independent physician scientist in the field of hepatology research. Michael has previously received PhD training in cellular and molecular pathology with a focus on liver disease. At the current time, he has completed clinical training in Pediatric Endocrinology and has designed a 5 year career development plan to provide additional training in bile acid metabolism and microbiome research. At the end of this career development award, he will become an independent investigator with his own lab program evaluating the developmental origins of liver disease. Dr. Nicholas Davidson, Chief of Gastroenterology at Washington University, will mentor the PI. Dr. Davidson is a well-known leader in intestinal and hepatic bile acid metabolism research and an experienced mentor. Dr. Phil Tarr, Chief of Pediatric Gastroenterology at Washington University, will serve as co-mentor for the PI. Dr. Tarr is a recognized leader in microbiome research which is a primary focus of this proposal. The PI will take advantage of the abundant basic science and clinical resources available at Washington University to develop his own clinically relevant basic research program. Obesity and its complications affect 78 million adults and 13 million children with an estimated economic impact of $2.0 trillion per year. Growing evidence supports that in utero and perinatal events drive risk for insulin resistance and obesity associated complications such as nonalcoholic fatty liver disease (NAFLD) in the offspring. Our preliminary findings indicate that alterations in bile acid homeostasis are associated with this increased risk. This proposal will focus on defining the mechanisms behind the observed alterations in bile acid homeostasis. I will utilize an established model of maternal high fat/high sugar diet exposure to test this hypothesis. In the first aim, I will evaluate cholesterol absorption, bile acid excretion, and bile acid metabolism/transport to define which are contributing to the increased bile acid pool size and composition. In the second aim, I will define whether vertical transmission of the microbiome occurs across generations and whether changes in the microbiome impact bile acid metabolism and metabolic liver disease in the offspring. In the third aim, I will evaluate the efficacy of targeting the bile acid pool size or pool composition as a preventative approach for metabolic liver disease offspring of obese dams. Specifically, I will treat offspring with a bile acid sequestrant (cholestyramine) or a hydrophilic bile acid (UDCA) prior to feeding a western diet, after which I will evaluate insulin resistance and steatosis. Identification of potentially pathogenic alterations in bile acid pool composition, metabolism, and/or transport will support further hypothesis driven research design to identify the mechanism of increased risk for disease progression. Once a mechanistic link is proven between altered bile acid metabolism in offspring and risk for NAFLD progression, this information will be used to design bile acid based preventative therapies to prevent disease progression in at risk patients.

项目概要/摘要该提案的主要目标是将首席研究员 Michael Thompson 博士培养成一名肝病学研究领域的独立医师科学家。迈克尔此前已获得博士学位细胞和分子病理学培训，重点关注肝脏疾病。目前，他已经完成了儿科内分泌学临床培训，并设计了 5 年职业发展计划，以提供胆汁酸代谢和微生物组研究方面的额外培训。在本次职业发展结束时获奖后，他将成为一名独立调查员，拥有自己的实验室计划，评估发育肝脏疾病的起源。华盛顿大学胃肠病学主任尼古拉斯·戴维森博士将指导 PI。戴维森博士是肠道和肝脏胆汁酸代谢研究领域的知名领导者，也是一位经验丰富的导师。华盛顿大学儿科胃肠病学主任 Phil Tarr 博士将担任 PI 的共同导师。塔尔博士是微生物组研究领域公认的领导者，微生物组研究是该领域的主要关注点提议。 PI 将利用丰富的基础科学和临床资源华盛顿大学制定了自己的临床相关基础研究计划。肥胖及其并发症影响着 7,800 万成年人和 1,300 万儿童，估计造成经济损失每年影响 2 万亿美元。越来越多的证据表明，子宫内和围产期事件会增加风险胰岛素抵抗和肥胖相关并发症，例如非酒精性脂肪肝（NAFLD）后代。我们的初步研究结果表明胆汁酸稳态的改变与此相关风险增加。该提案将侧重于定义观察到的胆汁变化背后的机制酸稳态。我将利用母亲高脂肪/高糖饮食暴露的既定模型来测试这一点假设。在第一个目标中，我将评估胆固醇吸收、胆汁酸排泄和胆汁酸代谢/运输来确定哪些因素导致胆汁酸池大小和组成增加。在第二个目标，我将定义微生物组的垂直传播是否发生在几代人之间，以及微生物组的变化是否会影响后代的胆汁酸代谢和代谢性肝病。在第三个目标，我将评估以胆汁酸池大小或池组成为目标的功效肥胖母猪后代代谢性肝病的预防方法。具体来说，我会对待后代在喂食西方饮食之前使用胆汁酸螯合剂（考来烯胺）或亲水性胆汁酸（UDCA），之后我将评估胰岛素抵抗和脂肪变性。鉴定潜在致病性改变胆汁酸池组成、代谢和/或运输将支持进一步的假设驱动的研究设计以确定疾病进展风险增加的机制。一旦机械联系被证明在后代胆汁酸代谢改变与 NAFLD 进展风险之间，将使用此信息设计基于胆汁酸的预防疗法，以预防高危患者的疾病进展。