AGEs/RAGE in Progressive NASH

 描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是最常见的肝脏疾病之一，可导致脂肪性肝炎(NASH)和肝硬变。根据目前的概念，脂肪变性的疾病进展是在多次“击中”之后发生的，但其中涉及的因素尚不清楚。NASH的临床表现是不同的，许多患者，特别是糖尿病患者，已经出现晚期脂肪性肝炎和纤维化。然而，II型糖尿病(DM)是坏死性炎症性疾病的主要危险因素；糖尿病与肝脏的促炎和纤维化活动之间的详细机制联系尚未明确。在这项应用中，我们提出了一种新的范例，在糖尿病患者中，NASH是作为一种导致纤维化的侵袭性炎症障碍而启动的。糖尿病会导致晚期糖基化终末产物(AGEs)的积累，这是血清蛋白非酶糖基化的结果。AGEs在NASH中的致病作用尚未明确，因此我们试图确定AGEs在肝脏中的细胞靶点，以及导致氧化、炎症和纤维化损伤的受体和信号通路。我们的主要目标是对AGEs启动肝细胞免疫原性细胞死亡以及随后的炎症和纤维化事件的核心作用提供机械性见解。我们将集中于1)确定肝细胞暴露于AGEs如何导致应激信号的诱导导致免疫原性细胞死亡和吞噬细胞的“Find-Me信号”，2)研究RAGE介导的凋亡肝细胞的拴系和吞噬(泡泡吞噬)以诱导巨噬细胞的炎症途径和纤维化。3)在体内模型中确定AGEs/RAGE对NASH炎症、氧化损伤、纤维化脂肪变性和胰岛素抵抗的影响。这些研究将大大增强我们对糖尿病在NASH中的促炎作用、AGE/RAGE信号的细胞特异性作用的理解，从而突出了开发有效治疗方案的未来途径。

 DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases that can lead to steatohepatitis (NASH) and cirrhosis. According to current concepts, disease progression from steatosis occurs after multiple "hits" but the factors implicated in this are poorly understood. The presentation of NASH is clinically heterogeneous, and many patients especially those with diabetes, present with already advanced steatohepatitis and fibrosis. Type II diabetes mellitus (DM) is a major risk factor for necroinflammatory disease however; the detailed mechanistic links between diabetes and the proinflammatory and fibrogenic activity in the liver have not been defined. In this application we propose a novel paradigm that in diabetics NASH is initiated as an aggressive inflammatory disorder that results in fibrosis. DM leads to the accumulation of advanced glycation end-products (AGEs) as a result of a non-enzymatic glycation of serum proteins. The pathogenic role of AGEs in NASH are not defined thus we seek to identify the cellular targets of AGEs in the liver, the receptors and signaling pathways responsible for oxidative, inflammatory and fibrogenic injury. Our main goal is to provide mechanistic insights on the central role of AGEs initiating immunogenic cell death of hepatocytes, and subsequent inflammatory and fibrogenic events. We will focus on 1) Determining how the exposure of hepatocytes to AGEs results in the induction of stress signaling leading to immunogenic cell death and exposure of "find-me signals" for phagocytes, 2) Studying RAGE-mediated tethering and engulfment (efferocytosis) of apoptotic hepatocytes priming macrophages for the induction of inflammatory pathways and fibrosis.; 3) To define the in vivo effects of AGEs/RAGE on inflammation, oxidative injury, fibrosis steatosis, and insulin resistance in NASH in in vivo models. These studies will significantly enhance our understanding the proinflammatory effects of diabetes in NASH, the cell-specific actions of AGE/RAGE signaling thus highlighting future avenues in developing effective treatment options.