Regulation of Lipid Metabolism by miR-29a within Hepatocytes

肝细胞内 miR-29a 对脂质代谢的调节

基本信息

批准号：
8487710
负责人：
Aras Nikodemas Mattis
金额：
$ 15.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487710
关键词：
Adult Affect African American Alleles American Animal Model Authorization documentation Automobile Driving Award Basic Science Biological Models Biology Biopsy Biopsy Specimen C57BL/6 Mouse California Candidate Disease Gene Cellular Stress Response Characteristics Cirrhosis Clinical Data Development Diabetes Mellitus Diet Disease Endotoxins Energy Intake Epidemic Family Fatty Liver Fatty acid glycerol esters Fibrosis Freezing Gene Expression Gene Targeting Genes Genetic Goals Health Hematoxylin and Eosin Staining Method Hepatic Hepatic Stellate Cell Hepatocyte High Prevalence Hispanics Histology Human Hypertriglyceridemia Individual Inflammation Insulin Resistance K-Series Research Career Programs Knock-out Lead Life Link Lipids Liver Liver Fibrosis Liver diseases Medical Research Mentors Metabolic Metabolic Diseases Metabolic syndrome MicroRNAs Mission Modeling Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Nutrition Disorders Obesity Overweight Pathologic Pathology Pathway Analysis Pathway interactions Patients Phenotype Physicians Plasma Population Postdoctoral Fellow Predisposition Prevalence Primary carcinoma of the liver cells Proteins Public Health Regulation Relative (related person)Research Research Methodology Research Personnel Research Project Grants Risk Role San Francisco Scientist Secondary to Staging Steatohepatitis Susceptibility Gene Techniques Testing Time Tissues Training Trichrome stain method Triglycerides Tumor Necrosis Factor Receptor United States National Institutes of Health Universities base burden of illness career cell type diabetes management dietary excess disability falls gastrointestinal gene discovery genome wide association study in vivo Model inhibitor/antagonist lipid metabolism lipoprotein lipase lipoprotein triglyceride liver biopsy liver metabolism liver transplantation member multidisciplinary nonalcoholic steatohepatitis patient oriented public health relevance research study uptake vector

项目摘要

DESCRIPTION (provided by applicant): This is an application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Aras Mattis, a Gastrointestinal/Liver Pathology Postdoctoral Fellow at the University of California, San Francisco (UCSF). This K08 award will provide the core support necessary to establish Dr. Mattis as an independent researcher and to achieve the following career goals over the five year term of this award: 1) Become an expert in liver biology, development, and disease research especially as related to FLD, NASH, and liver metabolism, 2) increase his understanding of metabolic lipid pathways and analysis, and 3) master techniques in gene and microRNA array analysis. To achieve these goals, Dr. Mattis has developed a plan and assembled a multidisciplinary advisory team of scientists and physician-scientists specializing in liver biology, hepatic lipid metabolism, and cellular stress responses. With the rising North American obesity epidemic, secondary health problems associated with increased caloric intake have become common including FLD. While not all overweight individuals are at risk for FLD, the proportion is estimated to affect approximately 20% of the US population. For those that do develop FLD, over time one-tenth of those will go on to develop NASH resulting in fibrosis, cirrhosis, and increased risk for hepatocellular carcinoma (HCC). The long-term goal is to understand the molecular mechanisms leading to FLD and NASH including the genes that increase susceptibility to the disease as well as those that are protective. The objective for this project is to understand the role of microRNA 29a (miR-29a) in FLD and NASH. The hypothesis is that miR-29a is a central genetic switch that regulates hepatic lipid uptake, liver fibrosis, and inflammation. The specific experimental aims of this project are to 1) establish the role of miR-29a in hepatic lipid metabolism by determining the genes directly regulated by miR-29a, 2) establish that miR-29a over-expression in the liver is hepato-protective in the liver of mice challenged by a western-diet, and 3) evaluate the relative levels of miR-29a in a set of liver biopsies from patients with spectrum of fatty liver disease. This career development award and project will not only provide crucial training for Dr. Mattis, but this research project will also evaluate the role of miR-29a a a central regulator that might explain all the different characteristics of NASH pathology. This research takes both a basic biology approach using a model organism as well as a patient-oriented biopsy approach with direct relevance to human FLD and NASH. This project follows the mission of the NIH and more specifically of the NIDDK to support medical research on metabolic diseases, obesity, and nutritional disorders.

描述（由申请人提供）：这是加州大学旧金山分校 (UCSF) 胃肠/肝脏病理学博士后研究员 Aras Mattis 博士的 K08 指导临床科学家研究职业发展奖申请。该 K08 奖项将为马蒂斯博士成为一名独立研究员提供必要的核心支持，并在该奖项的五年期限内实现以下职业目标： 1) 成为肝脏生物学、发育和疾病研究方面的专家，尤其是与FLD、NASH和肝脏代谢相关，2）增加对代谢脂质途径和分析的理解，3）掌握基因和microRNA阵列分析技术。为了实现这些目标，马蒂斯博士制定了一项计划，并组建了一个由专门研究肝脏生物学、肝脏脂质代谢和细胞应激反应的科学家和医师科学家组成的多学科咨询团队。随着北美肥胖流行率的上升，与热量摄入增加相关的继发性健康问题变得很常见，包括 FLD。虽然并非所有超重的人都有患 FLD 的风险，但据估计，该比例影响了大约 20% 的美国人口。对于那些确实患有 FLD 的人，随着时间的推移，其中十分之一将继续发展为 NASH，导致纤维化、肝硬化和肝细胞癌 (HCC) 风险增加。长期目标是了解导致 FLD 和 NASH 的分子机制，包括增加疾病易感性的基因以及具有保护作用的基因。该项目的目标是了解 microRNA 29a (miR-29a) 在 FLD 和 NASH 中的作用。假设认为 miR-29a 是调节肝脏脂质摄取、肝纤维化和炎症的核心基因开关。具体的该项目的实验目的是 1) 通过确定 miR-29a 直接调节的基因来确定 miR-29a 在肝脂质代谢中的作用，2) 确定 miR-29a 在肝脏中的过度表达在肝脏中具有肝保护作用。受到西方饮食挑战的小鼠肝脏，3) 评估脂肪肝患者的一组肝活检中 miR-29a 的相对水平。该职业发展奖和项目不仅将为 Mattis 博士提供重要的培训，而且该研究项目还将评估 miR-29a 的作用，miR-29a 是一种可能解释 NASH 病理学所有不同特征的中央调节因子。这项研究既采用了使用模型生物体的基本生物学方法，也采用了与人类 FLD 和 NASH 直接相关的以患者为导向的活检方法。该项目遵循 NIH，更具体地说是 NIDDK 的使命，支持代谢疾病、肥胖和营养失调的医学研究。