Regulation of lipid metabolism by macroautophagy

描述（由申请人提供）：该候选人是一名初级研究员，在非酒精性脂肪性肝病（NAFLD）、代谢综合征和自噬研究方面具有丰富的经验。然而，为了使申请人过渡到一个完全独立的调查员，额外的监督培训时期是必要的。Mark J. Czaja博士在肝脏生理学、NAFLD和自噬研究方面拥有丰富的研究经验，将成为本次额外培训的理想导师。该研究项目将在阿尔伯特·爱因斯坦医学院的Marion Bessin肝脏研究中心进行，该中心提供了一个科学激励和鼓舞人心的环境，并拥有完善的肝脏研究设施，非常适合研究细胞代谢和生理变化。建议的五年职业发展计划侧重于：i)赋予候选人在肝脏研究方面的强大背景；ii)提高他的研究技能和基础知识，以及学习新的实验方法；iii)促进与知名研究人员的富有成效的合作；iv)发展他的教学，培训和团队领导技能。当前研究项目的主要目标是了解巨噬通过器官特异性作用作为细胞脂质含量的关键调节剂的机制，从而导致代谢综合征的表现。我们建议通过肝细胞、脂肪细胞和下丘脑细胞以及自噬敲除小鼠模型来验证这一假设，以描绘自噬在调节全身能量含量和肝脏脂质积累的三个相互关联的器官中的功能。这些研究分为三个具体目标。首先，我们将确定巨噬是否调节脂肪性肝炎和肝脏胰岛素抵抗的发展。其次，我们将建立自噬通过影响脂肪细胞分化来调节脂肪组织质量和脂质含量。第三，我们将证明自噬调节下丘脑脂质代谢，以响应循环的营养物质，然后调节促氧肽的分泌和食物摄入。这些研究的最终目的是更好地了解三个相互关联的器官中调节脂质代谢和脂质积累的基本细胞机制，以便设计预防和治疗人类NAFLD的新策略。

DESCRIPTION (provided by applicant): The candidate is a junior researcher with considerable experience in studies of nonalcoholic fatty liver disease (NAFLD), metabolic syndrome and autophagy. However, in order for the applicant to transition into a fully independent investigator, an additional supervised training period is imperative. Dr. Mark J. Czaja has extensive research experience in the study of liver physiology, NAFLD and autophagy, will serve as an ideal mentor for this additional training. The research project will be carried out in the Marion Bessin Liver Research Center at the Albert Einstein College of Medicine which offers a scientifically motivating and inspiring environment and has a well-established liver research facility ideally suited to study altered cellular metabolism and physiology. The proposed five year career development plan is focused on: i) conferring upon the candidate a strong background in liver research, ii) improving his research skills and fundamentals as well as the learning of new experimental approaches, iii) facilitating productive collaborations with established researchers and iv) developing his teaching, training, and group leadership skills. The main goal of the current research project is to understand the mechanisms by which macroautophagy functions as a critical regulator of cellular lipid content through organ specific effects which lead to manifestations of the metabolic syndrome. We propose to test the hypothesis with studies in hepatocyte, adipocyte and a hypothalamic cells and autophagy knockout mouse models to delineate the function of autophagy in three interrelated organs that regulate whole body energy content and hepatic lipid accumulation. The studies are divided into three specific aims. First, we will determine whether macroautophagy regulates the development of steatohepatitis and hepatic insulin resistance. Second, we will establish that autophagy regulates adipose tissue mass and lipid content through effects on adipocyte differentiation. Third, we will demonstrate that autophagy regulates hypothalamic lipid metabolism in response to circulating nutrients, which then modulates orexigenic peptide secretion and food intake. The ultimate goal of these investigations is to better understand basic cellular mechanisms in three interrelated organs that regulate lipid metabolism and lipid accumulation in order to design new strategies for the prevention and treatment of human NAFLD. PUBLIC HEALTH RELEVANCE: Metabolic syndrome and NAFLD are prevalent clinical conditions that have no known treatment. Attempts to understand the mechanisms of lipid metabolism in three interrelated organs that crosstalk with each other to regulate lipid metabolism are critical to the development of new strategies for the prevention and treatment of NAFLD.