Rho-Dependent COX-2 Expression in Intestinal Cells

肠细胞中 Rho 依赖性 COX-2 表达

基本信息

批准号：
7456667
负责人：
Lee Warren Slice
金额：
$ 0.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-21 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456667
关键词：
Acute Agonist Authorization documentation California Cell Line Cells Cytoprotection Diarrhea Disclosure Doctor of Philosophy EGF gene Elements Epithelial Epithelial Cells Face Fibroblasts G-Protein-Coupled Receptors Gene Expression Growth Factor Guanine Nucleotide Exchange Factors Guanine Nucleotides Human Resources Immediate-Early Genes Inflammatory Inflammatory Bowel Diseases Instruction Intestinal Cancer Intestines Last Name Los Angeles Mediating Modeling Names Numbers Pathologic Processes Pathology Pathway interactions Phosphotransferases Physiological Processes Physiology Play Principal Investigator Printing Production Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Kinase Proteins Rattus Receptor Activation Regulation Research Personnel Research Project Grants Role Signal Pathway Signal Transduction Signal Transduction Pathway Slice Small Intestines Stimulus Testing Universities carcinogenesis cell motility cis acting element cyclooxygenase 1 cyclooxygenase 2 cytokine novel progesterone 11-hemisuccinate-(2-iodohistamine)programs promoter response rho

项目摘要

Prostaglandins (PGs) play a fundamental role in the physiology and pathology of the small intestine. PGs modulate various physiological processes including secretion, cytoprotection, epithelial and endothelial barrier function, and motility. Alterations in PG production is also implicated in pathological processes including intestinal carcinogenesis. PGs are produced by intestinal epithelial cells by cyclooxygenases (COX). Acute changes in PG levels in these cells are controlled by COX-2, which is rapidly induced as an immediate-early gene in response to multiple stimuli including inflammatory cytokines and growth factors. Despite the importance of COX-2 in intestinal physiology, little is known about the regulation of COX-2 gene expression in intestinal epithelial cells. Understanding the signaling pathways that regulate the expression of COX-2 in intestinal cells will be important for defining the loss of its control in pathology including intestinal cancer. The broad, long-term objective of this proposal is to elucidate the signal transduction pathways that mediate COX-2 expression in intestinal epithelial cells in response to agonists that act through G-protein coupled receptors (GPCRs). We have identified a new Rho-dependent signaling pathway, activated by agonists of GPCRs, that induces COX-2 expression in fibroblast cell lines. Therefore, we have proposed a model that envisages a novel Rho-dependent signaling cascade that is activated by GPCR agonists in their target intestinal epithelial cells. This proposal will examine the following hypotheses: 1) Agonist occupancy of GPCRs induces COX-2 expression via a Rho-dependent pathway, 2) Signaling by Rho and EGF synergistically induce COX-2 expression in intestinal cells, 3) GPCR activation of Rho is mediated by G_12/13 via Rho-specific guanine nucleotide exchange factors (GEFs) or Gcu t via PYK-2 and 4) COX-2 expression is mediated through unique, Rho-specific cis-acting elements on the COX-2 promoter. In order to test these hypotheses, we have formulated four specific aims, which are: 1)l)emonstrate and characterize GPCR-mediated COX-2 expression in normal rat intestinal epithelial cells. 2a)I)efine the role of Get2/13 signaling in COX-2 expression in intestinal epithelial cells. 2b) Derme the role of Gaq and Go,i signaling in COX-2 expression in intestinal epithelial cells. 3)Define the role of Rho and of Protein Kinases acting upstream and downstream of Rho in COX-2 expression in intestinal epithelial cells. 4) Characterize COX-2 promoter elements that are responsive to Rho. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Lee W. Slice, PhD University of California, Los Angeles Hal F. Yee, Jr, MD, PhD University of California, Los Angeles Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions, [] Yes [] No _ PHS 398 (Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b, Role on Project Principal Investigator Co-investigator Form Page 2 _ ¿ Principal Invostigator/Program Director (Last, first, middle): Slice, Lee Warren The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,

前列腺素（PGS）在小肠的生理和病理学中起着基本作用。 PGS调制各种物理过程，包括分泌，细胞保护，上皮和内皮屏障功能以及运动。 PG产生的改变也在包括肠道癌发生在内的病理过程中实施。 PG是由肠上皮细胞由环氧酶（COX）产生的。这些细胞中PG水平的急性变化由COX-2控制，Cox-2迅速诱导了直接至上的基因，以响应多种刺激（包括）炎性细胞因子和生长因子。尽管COX-2在肠道生理学中很重要，但知之甚少关于肠上皮细胞中Cox-2基因表达的调节。了解信号通路调节COX-2在肠细胞中的表达对于定义其病理中其控制的丧失至关重要包括肠癌。该提议的广泛长期目标是阐明信号转导响应通过G蛋白起作用的激动剂，介导肠上皮细胞中Cox-2表达的途径耦合受体（GPCR）。我们已经确定了一种新的Rho依赖性信号通路，被激动者激活 GPCR，影响成纤维细胞系中的COX-2表达。因此，我们提出了一个设想的模型 GPCR激动剂在其靶肠上皮细胞中激活的新型Rho依赖性信号级联。该提案将检查以下假设：1）GPCR的激动剂占用率通过A诱导COX-2表达 RHO依赖性途径，2）Rho和EGF信号传导在肠细胞中诱导COX-2表达，3） GPCR激活RHO是由G_12/13通过Rho特异性鸟嘌呤核丁基交换因子（GEFS）或GCU T介导的通过PYK-2和4）Cox-2的表达是通过COX-2上的独特的，特异性的顺式作用元素介导的发起人。为了检验这些假设，我们提出了四个具体目标，即：1）l）示出来表征正常大鼠肠上皮细胞中GPCR介导的COX-2表达。 2a）i）efine的作用肠上皮细胞中COX-2表达中的GET2/13信号传导。 2b）真皮Gaq和Go的作用，我发出信号在肠上皮细胞中的COX-2表达中。 3）定义Rho和蛋白激酶作用的作用在肠上皮细胞中，Rho在COX-2表达中的上游和下游。 4）表征COX-2 对Rho响应的启动子元素。关键人员。请参阅说明。根据需要使用延续页面，以下面显示的格式提供所需的信息。从首席研究员开始。按字母顺序列出所有其他关键人员，首先姓氏。名称组织 Lee W. Slice，加利福尼亚大学博士，洛杉矶加利福尼亚大学博士，洛杉矶大学医学博士Hal F. Yee，医学博士披露许可声明。仅适用于SBIR/STTR。请参阅说明，[]是[]否 _ PHS 398（Rev. 05/01）第2页整个应用程序中的底部连续数字页面。请勿使用3A，3B等后缀项目的角色首席研究员共同研究器表2 _ „主要的InvoStigator/Program总监（最后，第一，中间）：Slice，Lee Warren 必须在每个印刷页面的顶部和每个延续页面的顶部提供主要调查员/计划主管的名称。研究赠款目录页码脸部页面................................................................................................................................................................................................................................................................................................................................................................................... 描述，