The Role of NOX2 in Liver Fibrosis

描述（由申请人提供）： 肝纤维化是一个复杂的过程，其包括一系列事件，包括炎性细胞浸润和产生基质的间充质细胞的增殖，以及细胞外基质（ECM）组分（包括I型胶原）的积累增加。在纤维化过程的中心是肝星状细胞（HSC）。最近，我们已经表明，HSC吞噬凋亡小体（AB）从垂死的肝细胞，这诱导NADPH氧化酶（NOX）的激活，并导致超氧化物的生产和释放到细胞内和细胞内环境。然后细胞内超氧化物诱导前胶原α 1（I）上调，从而促进纤维化过程. HSC的吞噬作用可能是一种常见的、普遍的途径，导致纤维化，与肝病的病因无关，将慢性肝损伤与肝细胞凋亡联系起来，以清除AB并导致瘢痕形成。由于NOX活化似乎是诱导HSC活化的关键因素，并且尚不清楚吞噬NOX（NOX 2）是否在吞噬中起作用，因此我们的假设是AB吞噬特异性地导致NOX 2活化，并且这通过Rac-GT β活化信号传导途径，导致HSC的运动性和活化增加。本提案的具体目标是回答由这一假设产生的两个关键问题： 1. NOX 2是否在HSC吞噬AB中起作用？和 2. PS与HSC上的受体（PS-R）结合，以及随后的AB吞噬，是否诱导NOX 2和下游信号通路？ 在本提案中，我们开发了新的研究领域，这些领域是原始K 08申请中描述的具体目标的自然延伸，并基于K 08资助中描述的研究数据。研究所提出的信号事件的重要性是增强的事实，这些可能代表共同的途径，在肝纤维化，独立的病因。

DESCRIPTION (provided by applicant): Liver fibrogenesis is a complex process which comprises of a sequence of events including inflammatory cell infiltration and proliferation of matrix-producing mesenchymal cells, with an increased accumulation of the extracellular matrix (ECM) components, including type I collagen. At the center of the fibrogenic process are the hepatic stellate cells (HSC). Recently we have shown that HSC phagocytose apoptotic bodies (AB) from dying hepatocytes and this induces NADPH oxidase (NOX) activation and resulting superoxide production and release both into the intracellular and intracellular milieu. Intracellular superoxide then induces procollagen a 1(I) upregulation, thereby contributing to the fibrogenic process. Phagocytosis by HSC is likely to be a common, universal pathway leading to fibrosis independent of the etiology of the liver disease, linking chronic liver injury with apoptosis of hepatocytes to clearance of AB with resulting scar formation. As NOX activation appears to be a critical element in inducing HSC activation, and it is unknown whether the phagocytic NOX (NOX2) plays role in engulfment, our HYPOTHESIS is that AB engulfment leads specifically to NOX2 activation, and that this via the Rac-GTPase activates signaling pathways, leading to increased motility and activation of HSC. The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is NOX2 playing a role in the phagocytosis of AB in HSC? And 2. Does PS binding to its receptor (PS-R) on HSC, and the subsequent engulfment of AB, induce NOX2 and downstream signaling pathways? In this proposal we develop new areas of investigation that are the natural extension of the specific aims described in the original K08 application, and based on data derived from the studies described in the K08 grant. The importance of studying the proposed signaling events is enhanced by the fact that these likely represent common pathways in liver fibrosis, independent of etiology.