The involvement of RNase L in the pathogenesis of inflammatory bowel disease

描述（由申请人提供）：RNase L是一种干扰素诱导酶，在肠和肠上皮细胞中高度表达。然而，其在肠上皮细胞中的作用在很大程度上是未知的。在本项目中，我们假设RNase L调控促炎基因的表达，介导肠黏膜表面上皮细胞的炎症反应和凋亡。缺乏RNase L可减轻炎症性肠病（IBD）。这一假说主要基于有证据表明RNase L是肿瘤坏死因子- α (tnf - α)、ifn - γ诱导蛋白-10 （IP-10）和环氧化酶-2 （Cox-2）等促炎基因表达的调节因子，并在细胞凋亡中发挥重要作用。我们的长期目标是阐明RNase L在IBD发病机制中的作用，作为开发能够减轻疾病过程的治疗方法的必要前提。为了验证我们的假设，提出了两个具体目标。在第一个特定目的中，将评估RNase L在肠道炎症反应和上皮细胞凋亡中的作用，并通过RNase L缺失小鼠来确定RNase L在IBD发病机制中的作用。在第二个特定目标中，RNase L调节tnf - α表达的分子机制将被阐明。旨在了解RNaseL在肠上皮细胞炎症和凋亡中的作用及其机制的研究不仅将为IBD的病因提供新的见解，而且还将批判性地评估RNaseL作为预防和/或治疗IBD的新靶点的意义。

DESCRIPTION (provided by applicant): RNase L, an interferon-inducible enzyme, is highly expressed in the intestine and intestinal epithelial cells. However, its roles in intestinal epithelial cells are largely unknown. In this project, we hypothesize that RNase L regulates the expression of proinflammatory genes, mediates the inflammatory responses and apoptosis in epithelial cells of intestinal mucosal surface. Lack of RNase L attenuates inflammatory bowel diseases (IBD). This hypothesis is mainly based on the evidence that RNase L is a regulator of the expression of certain proinflammatory genes such as tumor necrosis factor-alpha (TNF-alpha), IFN-gamma inducible protein-10 (IP-10) and cycloxygenase-2 (Cox-2), and plays an important role in cell apoptosis. Our long-term goal is to elucidate the role of RNase L in the pathogenesis of IBD as a necessary prerequisite to the development of therapeutic methods capable of attenuating the disease process. Two specific aims are proposed to test our hypothesis. In the first specific aim, the role of RNase L in intestinal inflammatory responses and epithelial cell apoptosis will be assessed, and the contribution of RNase L to the pathogenesis of IBD will be determined by using RNase L null mice. In the second specific aim, the molecular mechanism by which RNase L regulates the expression of TNF-alpha will be elucidated. Studies proposed to understand the role of RNase L in inflammation and apoptosis of intestinal epithelial cells, as well as the mechanisms involved will not only provide new insight into the etiology of IBD, but also critically evaluate the significance of RNaseL as a novel target for prevention and/or treatment of IBD. PUBLIC HEALTH RELEVANCE: The objectives in the proposed study are to determine the role of RNase L in the pathogenesis of inflammatory bowel disease and elucidate the molecular mechanism by which RNase L mediates the expression of inflammatory genes.