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: 8899525
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899525
• 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; 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Aras Mattis博士的K 08指导临床科学家研究职业发展奖申请，Aras Mattis博士是加州大学旧金山分校（UCSF）的胃肠道/肝脏病理学博士后研究员。弗朗西斯科（UCSF）。该K 08奖项将提供必要的核心支持，以使马蒂斯博士成为一名独立研究人员，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，特别是与FLD、NASH和肝脏代谢相关的专家，2）增加对代谢脂质途径和分析的理解，掌握基因和microRNA芯片分析技术。为了实现这些目标，Mattis博士制定了一项计划，并组建了一个由科学家和医生科学家组成的多学科咨询团队，专门研究肝脏生物学，肝脏脂质代谢和细胞应激反应。 随着北美肥胖流行病的上升，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。虽然并非所有超重的人都有患FLD的风险，但据估计，这一比例影响了约20%的美国人口。对于那些确实发展FLD的人，随着时间的推移，十分之一的人将继续发展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，包括增加疾病易感性的基因以及保护性基因。该项目的目的是了解microRNA 29 a（miR-29 a）在FLD和NASH中的作用。假设miR-29 a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 该项目的实验目的是1）通过确定miR-29 a直接调节的基因来确定miR-29 a在肝脂质代谢中的作用，2）确定miR-29 a在肝脏中的过表达在受到西方饮食攻击的小鼠的肝脏中具有保肝作用，和3）评估来自具有脂肪肝疾病谱的患者的一组肝活检中miR-29 a的相对水平。 这个职业发展奖和项目不仅将为Mattis博士提供重要的培训，而且这个研究项目还将评估miR-29 a的作用，miR-29 a是一种可能解释NASH病理学所有不同特征的中央调节因子。这项研究采用了使用模式生物的基本生物学方法以及与人类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的使命，更具体地说，是NIDDK支持代谢疾病、肥胖和营养失调的医学研究。