Effect of alcohol on obesity related liver disease: Role of intestinal metabonome

酒精对肥胖相关肝病的影响：肠道代谢组的作用

• 批准号: 8519185
• 负责人: Puneet Puri
• 金额: $ 16.74万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519185
• 关键词: Address; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; American; Apoptosis; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Award; Basic Science; Bioinformatics; Biological Markers; Cells; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials Network; Collaborations; Commit; Communities; Community Networks; Complex; Data; Development; Dimensions; Disease; Disease Pathway; Economics; Eicosanoids; Elements; Environment; Exposure to; Fatty Liver; Fingerprint; Foundations; Funding; Future; Gene Expression Profile; Genes; Genotype; Goals; Growth; Hepatic; Heterogeneity; Histology; Individual; Indoles; Inflammation; Inflammatory; Interdisciplinary Study; Intestines; K-Series Research Career Programs; Knowledge; Lead; Length; Link; Lipoxygenase; Literature; Liver diseases; Malignant neoplasm of liver; Mentors; Methods; Molecular Biology Techniques; National Institute of Drug Abuse; Obesity; Obesity associated liver disease; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Pilot Projects; Plasma; Propionic Acids; Public Health; Publishing; Research; Research Training; Risk; Role; Scientist; Severities; Staging; Strategic Planning; Systems Biology; Taxonomy; Testing; Time; Training; Training Programs; Translational Research; United States National Institutes of Health; Urine; Work; alcohol effect; base; cost; drinking behavior; experience; high risk drinking; high throughput technology; insight; liquid chromatography mass spectrometry; liver injury; macrophage; metabolomics; microbial; microbiome; multidisciplinary; novel; patient oriented; pyrosequencing; skills; social; stem; treatment program

DESCRIPTION (provided by applicant): This K23 application describes a five year mentored training program. The application has two main objectives. First, it will provide the PI with protected time to complete an integrated research and training program guided by multidisciplinary team of mentors. This will include use of high throughput technologies, basic molecular biology techniques, bioinformatics and systems biology approach to study intestinal microbiomics, metabolomics, and interactions of alcohol and obesity related to liver disease. The PI will also complete formal coursework leading to a Masters in Clinical and Translational Research. In addition, the research utilizes an established network of community treatment programs, providing a unique opportunity for the PI to put new knowledge into actual practice. Taken together, this rigorous training program will provide the PI with information and experience integral to his transition from mentored scientist to independent research physician. The second objective is to investigate the effect of alcohol on obesity related liver disease. The PI will focus on the hypothesis that "In obese subjects, alcohol consumption alters the circulating profile of metabolites of intestinal microbial origin. Specific differentially expresse intestinal microbiome- derived metabolites promote development of fatty liver disease by directly activating disease related pathways (steatosis, inflammation, apoptosis etc.) and/or indirectly by activation of inflammatory cells". The proposed research has two specific aims: (1) to phenotype the intestinal metabonome in lean and obese subjects with varying amounts and patterns of alcohol consumption, and (2) to define how regular alcohol intake increases the development and severity of fatty liver disease in obese subjects. The research will interface directly with coe elements of the PI's training plan and is expected to demonstrate that alcohol consumption in obese subjects will alter the profile of intestinal microbiome and systemic metabolome that will modulate hepatic transcriptome and activate disease pathways over and above those seen in obesity. The activation of these pathways can promote liver disease in obese patients with alcohol use. These results will provide novel insights into (1) understanding mechanisms of how alcohol and obesity interact to promote liver disease, (2) development of biomarkers to identify those at risk or have developed liver disease, and (3) identification of specific targets for therapy. The proposed research will address the biologically and behaviorally complex interaction of alcohol and obesity as they relate to liver disease. This is directly aligned with te priorities of the NIH and contribute to their efforts to encourage and support growth of translational scientists, committed to bridging the gap between basic and clinical/community research and treatment.

描述（由申请人提供）：此 K23 申请描述了一个为期五年的指导培训计划。该应用程序有两个主要目标。首先，它将为 PI 提供受保护的时间来完成由多学科导师团队指导的综合研究和培训计划。这将包括使用高通量技术、基本分子生物学技术、生物信息学和系统生物学方法来研究肠道微生物组学、代谢组学以及与肝病相关的酒精和肥胖的相互作用。 PI 还将完成正式课程，获得临床和转化研究硕士学位。此外，该研究利用了已建立的社区治疗计划网络，为 PI 将新知识付诸实际实践提供了独特的机会。总而言之，这项严格的培训计划将为 PI 提供从受指导的科学家到独立研究医生过渡过程中不可或缺的信息和经验。第二个目标是研究酒精对肥胖相关肝病的影响。该 PI 将重点关注以下假设：“在肥胖受试者中，饮酒会改变肠道微生物来源的代谢物的循环特征。特异性差异表达的肠道微生物组衍生的代谢物通过直接激活疾病相关途径（脂肪变性、炎症）来促进脂肪肝疾病的发展。 、细胞凋亡等）和/或间接通过炎症细胞的激活”。拟议的研究有两个具体目标：（1）对不同饮酒量和模式的瘦人和肥胖受试者的肠道代谢组进行表型分析，以及（2）确定经常饮酒如何增加脂肪肝疾病的发展和严重程度。肥胖受试者。该研究将直接与 PI 培训计划的 coe 要素相结合，预计将证明肥胖受试者的饮酒将改变肠道微生物组和全身代谢组的概况，从而调节肝脏转录组并激活肥胖中所见的疾病途径。这些途径的激活可以促进肥胖饮酒患者的肝脏疾病。这些结果将为以下方面提供新的见解：（1）了解酒精和肥胖如何相互作用促进肝病的机制，（2）开发生物标志物来识别那些有肝病风险或已患肝病的人，以及（3）确定治疗的具体靶点。拟议的研究将解决酒精和肥胖在生物学和行为上的复杂相互作用，因为它们与肝病有关。这与 NIH 的优先事项直接一致，并有助于他们鼓励和支持转化科学家的成长，致力于缩小基础和临床/社区研究和治疗之间的差距。