Regulation of Lipid Metabolism by miR-29a within Hepatocytes

肝细胞内 miR-29a 对脂质代谢的调节

• 批准号: 9116129
• 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
• 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/9116129
• 关键词: Adult; Advisory Committees; Affect; African American; Alleles; American; Animal Model; 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 Chips; 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; LoxP-flanked allele; 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; 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; overexpression; patient oriented; research study; uptake; vector; western diet

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）：这是一份针对加州大学旧金山分校（UCSF）胃肠道/肝脏病理学博士后Aras Mattis博士的K08指导临床科学家研究职业发展奖的申请。K08奖将为马蒂斯博士提供必要的核心支持，使他成为一名独立的研究人员，并在该奖项的五年任期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，特别是与FLD、NASH和肝脏代谢相关的研究；2)增加他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，并组建了一个由肝脏生物学、肝脂质代谢和细胞应激反应方面的科学家和内科科学家组成的多学科咨询团队。随着北美肥胖症的流行，与热量摄入增加相关的继发性健康问题已经变得普遍，包括FLD。虽然不是所有超重的人都有患FLD的风险，但据估计，这一比例影响了大约20%的美国人口。对于那些确实发展为FLD的患者，随着时间的推移，其中十分之一的人会发展为NASH，导致纤维化、肝硬化和肝细胞癌（HCC）的风险增加。长期目标是了解导致FLD和NASH的分子机制，包括增加对疾病易感性的基因以及那些具有保护作用的基因。该项目的目的是了解microRNA 29a （miR-29a）在FLD和NASH中的作用。假设miR-29a是调节肝脏脂质摄取、肝纤维化和炎症的中心遗传开关。具体的