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

RNase L参与炎症性肠病发病机制

基本信息

批准号：
8036416
负责人：
AIMIN ZHOU
金额：
$ 33.63万
依托单位：
CLEVELAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8036416
关键词：
Apoptosis Attenuated Bone Marrow Cell Proliferation Cells Chronic Colon Colon Carcinoma Data Development Disease Embryo Enzymes Epithelial Cells Etiology Fibroblasts Fissure in Ano Fistula Gene Expression Gene Expression Regulation Genes Goals Immune Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interferon Type II Interferons Intestines JUN gene Knockout Mice Link Mediating Methods Molecular Mus Obstruction Pathogenesis Pathway interactions Play Prevention Principal Investigator Process Proteins RNase 2 Relapse Resistance Ribonucleases Risk Role Signal Pathway Sodium Dextran Sulfate Surface Testing Tumor Necrosis Factor-alpha Ulcer Virus Diseases base chemokine cytokine insight macrophage novel novel therapeutics pppA(2&apos p5&apos A)n-dependent ribonuclease programs stress-activated protein kinase 1 therapeutic development

项目摘要

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.

描述（由申请人提供）：RNase L是干扰素诱导的酶，在肠道和肠上皮细胞中高度表达。然而，它在肠上皮细胞中的作用在很大程度上是未知的。在这个项目中，我们假设RNase L调节促炎基因的表达，介导肠粘膜表面上皮细胞的炎症反应和凋亡。缺乏RNase L会减弱炎症性肠病（IBD）。该假设主要基于以下证据：RNase L是某些促炎基因（例如肿瘤坏死因子-Alpha（TNF-Alpha），IFN-Gamma诱导蛋白10（IP-10）（IP-10）和环氧酶-2（COX-2）的调节剂，以及在细胞中起重要作用。我们的长期目标是阐明RNase L在IBD发病机理中的作用，这是发展能够衰减疾病过程的治疗方法的必要先决条件。提出了两个具体目标来检验我们的假设。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，RNase L对IBD发病机理的贡献将通过使用RNase LNABE LINEL小鼠确定。在第二个特定目的中，将阐明RNase l调节TNF-α表达的分子机制。提议了解RNASE L在肠上皮细胞的炎症和凋亡中的作用以及所涉及的机制的研究不仅将提供对IBD病因的新见解，而且还将批判性地评估RNASEL作为IBD预防和/或治疗IBD的新目标的重要性。公共卫生相关性：拟议研究的目标是确定RNase L在炎症性肠病的发病机理中的作用，并阐明RNase L介导炎症基因表达的分子机制。