Regulation of TNF-alpha by Integrin-Mediated Matrix Signaling

整合素介导的基质信号传导对 TNF-α 的调节

基本信息

批准号：
7860286
负责人：
LESTER F LAU
金额：
$ 31.09万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-09 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860286
关键词：
Alleles Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Area Arthritis Atherosclerosis Autoimmunity Binding Biological Biological Process Biology Cell Death Cessation of life Clinical Diabetes Mellitus Disease Environment Equilibrium Extracellular Matrix Family Family member Fibroblasts Generations Genetic Transcription Genomics Health Helper-Inducer T-Lymphocyte Heparan Sulfate Proteoglycan Host Defense Human Immunity Inflammation Inflammatory Bowel Diseases Integrin alpha Chains Integrins Life Light MAPK8 gene Malignant Neoplasms Mediating Modeling Mus Natural Immunity Normal Cell Organogenesis Pathway interactions Physiological Play Process Protein Biosynthesis Proteins Reactive Oxygen Species Regulation Research Resistance Rheumatoid Arthritis Role Septic Shock Signal Pathway Signal Transduction Specific qualifier value TNFSF10 gene Testing Therapeutic Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Viral Work Wound Healing allograft rejection cell type connective tissue growth factor cytokine cytotoxicity in vivo inhibitor/antagonist interest mouse model mutant novel programs receptor response to injury syndecan-4 synergism

项目摘要

DESCRIPTION (provided by applicant): Cytokines of the tumor necrosis factor (TNF) family play critical roles in the regulation of inflammation, host defense and immunity, and can induce programmed cell death in a cell type- and context-dependent manner. TNFa is a potent activator of NFicB, which leads to the synthesis of multiple anti-apoptotic and proinflammatory factors. Consequently, TNFa induces apoptosis in most cell types only when NFicB signaling or de novo protein synthesis is blocked, and how it triggers apoptosis in vivo is not well understood. Recently, we have shown that the appropriate extracellular matrix environment can override the pro-survival effects of NFicB, enabling TNFa to induce apoptosis without perturbation of either NFxB-induced transcription or cfe novo protein synthesis. The presence of the matrix proteins CCN1 (CYR61), CCN2 (CTGF), or CCN3 (NOV) enables TNFa to induce apoptosis in the otherwise resistant primary human fibroblasts. CCN1 synergizes with TNFa through binding to integrins avf35> aepi and the heparan sulfate proteoglycan syndecan-4, leading to the reactive oxygen species (ROS)-dependent biphasic activation of JNK necessary for apoptosis. Furthermore, mice with the genomic Ccn1 locus replaced with an apoptosis-defective Ccn1 allele are severely blunted in TNFa-induced apoptosis, indicating that CCN1/TNFa synergism is an important apoptotic pathway in vivo. Thus, the extracellular matrix microenvironment can profoundly regulate the apoptotic activity of TNFa, and dictate whether TNFa executes a pro-life or pro-death program. In this application, we propose to investigate this apoptotic interaction between TNFa and CCN1 in three specific aims: 1. to elucidate how the multiple CCN1 receptors interact; 2. to analyze how TNFa- and CCN1-induced signaling pathways converge; and 3. to examine the physiological significance of TNFa-CCN1 interactions in vivo. We anticipate that these studies will yield important new information on how the activities of TNF cytokines can be contextually regulated by the extracellular matrix, and shed light on the many disease processes in which TNFa plays a role.

描述（由申请人提供）：肿瘤坏死因子（TNF）家族的细胞因子在调节炎症，宿主防御和免疫力的调节中起关键作用，并且可以以细胞类型和上下文依赖性方式诱导程序性细胞死亡。 TNFA是NFICB的有效活化剂，可导致多种抗凋亡和促炎因子的合成。因此，仅当NFICB信号传导或从头蛋白质的合成被阻断以及如何触发体内凋亡时，TNFA才会在大多数细胞类型中诱导凋亡。最近，我们已经表明，适当的细胞外基质环境可以覆盖NFICB的生存作用，从而使TNFA能够诱导凋亡而不会扰动NFXB诱导的转录或CFE NOVO NOVO蛋白合成。基质蛋白CCN1（CYR61），CCN2（CTGF）或CCN3（NOV）的存在使TNFA能够在原本抗性的原代人成纤维细胞中诱导凋亡。 CCN1通过与整联蛋白AVF35> AEPI和硫酸乙酰肝素蛋白聚糖syndecan-4结合而与TNFA协同，从而导致反应性氧（ROS）依赖性双相激活JNK所必需的JNK。此外，用基因组CCN1基因座取代的小鼠被TNFA诱导的细胞凋亡中严重钝化，表明CCN1/TNFA协同作用是重要的凋亡途径。因此，细胞外基质微环境可以深刻地调节TNFA的凋亡活性，并决定TNFA是否执行亲生命或亲死亡程序。在此应用中，我们建议在三个特定目标中研究TNFA和CCN1之间的这种凋亡相互作用：1。阐明多个CCN1受体如何相互作用； 2。分析TNFA和CCN1诱导的信号通路的收敛方式； 3。检验体内TNFA-CCN1相互作用的生理意义。我们预计，这些研究将产生有关如何通过细胞外基质来调节TNF细胞因子活动的重要新信息，并阐明TNFA起作用的许多疾病过程。