Mechanisms of Hepatic Steatosis Prevention

预防肝脏脂肪变性的机制

• 批准号: 6857929
• 负责人: MARK PUDER
• 金额: $ 12.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857929
• 关键词: cytokine; disease /disorder prevention /control; enzyme activity; enzyme induction /repression; fatty liver; genetically modified animals; laboratory mouse; lipid metabolism; liver metabolism; metalloendopeptidases; nutrition related tag; parenteral feedings; pathogenic diet; pathologic process; protease inhibitor; therapy adverse effect; triglycerides

DESCRIPTION (provided by applicant): Parental nutrition is life-saving but may produce severe liver injury, resulting in high morbidity and mortality in children. Long-term parenteral nutrition may also produce a slowly progressive liver injury in many adults. Since the development of parenteral nutrition over thirty years ago, there have been few improvements in the prevention and treatment of this liver injury. My primary career objective is to become an independent investigator conducting basic and translational research that advances the development of new therapies in the prevention and treatment of this often-fatal complication of parenteral nutrition. As steps toward this goal, I hope to gain additional training in basic lipid metabolism and the broad field of the biochemistry of matrix metalloproteinases. To guide me in my pursuit of these goals, I have chosen two outstanding recognized mentors and scientists, Dr. Bruce Bistrian and Dr. Marsha Moses. Together with Dr. Judah Folkman, they will also form my advisory committee. I have arranged for courses, conferences and meetings to complement these goals. My proposed research focuses on three aims. First, I intend to determine how matrix metalloproteinase inhibitors prevent steatosis and liver injury in our animal model utilizing in vivo lipid studies and in vitro enzymatic methods to study lipid synthesis, oxidation, and secretion of triglycerides from the liver. Second, I intend to determine the role of specific cytokines in the development of steatosis and its prevention utilizing genetically manipulated mice with and without matrix metalloproteinase inhibitors. Third, I intend to determine the transcription, protein levels, and enzymatic activity of specific metalloproteinases important in the development, prevention, and reversal of steatosis and steatohepatitis. This award would provide me with protected time to pursue these research and training objectives, and greatly facilitate my transition to an independent researcher in the study of this devastating disease

描述（由申请人提供）： 父母营养可以挽救生命，但可能造成严重的肝损伤，导致儿童的高发病率和死亡率。长期肠外营养也可能在许多成人中产生缓慢进行性肝损伤。自从30多年前肠外营养的发展以来，这种肝损伤的预防和治疗几乎没有改善。我的主要职业目标是成为一名独立的研究者，进行基础和转化研究，促进新疗法的开发，以预防和治疗这种经常致命的肠外营养并发症。为了实现这个目标，我希望在基础脂质代谢和基质金属蛋白酶生物化学的广泛领域获得额外的培训。为了引导我追求这些目标，我选择了两位杰出的公认导师和科学家，布鲁斯·比斯特里安博士和玛莎·摩西博士。他们还将与Judah Folkman博士一起组成我的咨询委员会。我已经安排了课程，会议和会议，以补充这些目标。我的研究主要集中在三个方面。首先，我打算确定基质金属蛋白酶抑制剂如何防止脂肪变性和肝损伤，在我们的动物模型利用体内脂质研究和体外酶的方法来研究脂质合成，氧化和分泌的甘油三酯从肝脏。其次，我打算确定特定的细胞因子在脂肪变性的发展和预防中的作用，利用基因操作的小鼠与基质金属蛋白酶抑制剂。第三，我打算确定在脂肪变性和脂肪性肝炎的发展、预防和逆转中重要的特定金属蛋白酶的转录、蛋白水平和酶活性。这个奖项将为我提供受保护的时间来追求这些研究和培训目标，并极大地促进我过渡到一个独立的研究人员在研究这种毁灭性的疾病