Regulation of Lipid Metabolism by miR-29a within Hepatocytes

描述（由申请人提供）：这是加州大学旧金山弗朗西斯科（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奖项将提供必要的核心支持，以建立马蒂斯博士作为一个独立的研究人员，并实现在该奖项的五年任期以下职业目标：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 29a（miR-29a）在FLD和NASH中的作用。假设是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-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。

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.