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: 9028594
• 负责人: Aras Nikodemas Mattis
• 金额: $ 0.15万
• 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/9028594
• 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K08指导的临床科学家研究职业发展奖Aras Mattis博士，Aras Mattis博士是加利福尼亚大学旧金山分校（UCSF）的胃肠道/肝病理学家。 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.为了实现这些目标，Mattis博士制定了一项计划，并组建了一个科学家和医师科学家的多学科咨询团队，专门研究肝生物学，肝脂质代谢和细胞压力反应。 随着北美肥胖症的上升，与卡路里摄入量增加有关的二级健康问题已成为FLD，包括FLD。尽管并非所有超重的人都有FLD的风险，但估计该比例会影响美国人口的20％。对于那些确实发展FLD的人，随着时间的流逝，其中十分之一将继续发展纳什，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以及保护性易感性的基因。该项目的目的是了解MicroRNA 29a（miR-29a）在FLD和NASH中的作用。假设是miR-29a是一种调节肝脂质摄取，肝纤维化和炎症的中心遗传转换。 具体 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. 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，是一个可以解释NASH病理学所有不同特征的中心调节器。这项研究既采用了使用模型生物体的基本生物学方法，又采用了与人类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的使命，更具体地说是NIDDK，以支持有关代谢疾病，肥胖和营养疾病的医学研究。