AGEs/RAGE in Progressive NASH

 描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是可导致脂肪性肝炎（NASH）和肝硬化的最常见肝病之一。根据目前的概念，脂肪变性的疾病进展发生在多次“打击”之后，但对此涉及的因素知之甚少。NASH的表现在临床上是异质性的，许多患者，特别是糖尿病患者，表现为已经晚期的脂肪性肝炎和纤维化。然而，II型糖尿病（DM）是坏死性炎症疾病的主要风险因素;糖尿病与肝脏中促炎和纤维化活性之间的详细机制联系尚未确定。在本申请中，我们提出了一种新的范例，即在糖尿病患者中，NASH作为导致纤维化的侵袭性炎症性疾病而启动。DM导致血清蛋白非酶糖化导致晚期糖基化终产物（AGEs）的积累。AGEs在NASH中的致病作用尚未确定，因此我们试图确定AGEs在肝脏中的细胞靶点，负责氧化，炎症和纤维化损伤的受体和信号传导途径。我们的主要目标是提供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中心作用的机制见解。我们将集中于1）确定肝细胞暴露于AGEs如何导致诱导应激信号传导，导致免疫原性细胞死亡和吞噬细胞暴露“发现我信号”，2）研究RAGE介导的凋亡肝细胞的束缚和吞噬（巨噬细胞吞噬），引发巨噬细胞诱导炎症途径和纤维化。3)在体内模型中确定AGEs/AGEs对NASH中炎症、氧化损伤、纤维化脂肪变性和胰岛素抵抗的体内作用。这些研究将显著增强我们对糖尿病在NASH中的促炎作用的理解，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.