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：
7929741
负责人：
LESTER F LAU
金额：
$ 23.49万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929741
关键词：
Alleles Allografting 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 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）家族的细胞因子在炎症、宿主防御和免疫的调节中发挥着关键作用，并且可以以细胞类型和环境依赖性方式诱导程序性细胞死亡。 TNFa 是 NFicB 的有效激活剂，可导致多种抗凋亡和促炎因子的合成。因此，只有当 NFicB 信号传导或蛋白质从头合成被阻断时，TNFa 才会在大多数细胞类型中诱导细胞凋亡，而它如何在体内触发细胞凋亡尚不清楚。最近，我们发现适当的细胞外基质环境可以克服 NFicB 的促生存作用，使 TNFa 能够诱导细胞凋亡，而不干扰 NFxB 诱导的转录或 cfe novo 蛋白质合成。基质蛋白 CCN1 (CYR61)、CCN2 (CTGF) 或 CCN3 (NOV) 的存在使得 TNFa 能够诱导原本耐药的原代人类成纤维细胞凋亡。 CCN1 通过与整合素 avf35> aepi 和硫酸乙酰肝素蛋白聚糖 syndecan-4 结合而与 TNFa 协同作用，导致细胞凋亡所需的活性氧 (ROS) 依赖性双相激活 JNK。此外，基因组 Ccn1 位点被凋亡缺陷型 Ccn1 等位基因取代的小鼠在 TNFa 诱导的细胞凋亡中严重减弱，表明 CCN1/TNFa 协同作用是体内重要的凋亡途径。因此，细胞外基质微环境可以深刻调节TNFa的凋亡活性，并决定TNFa是否执行促生命或促死亡程序。在本申请中，我们建议以三个具体目标研究 TNFa 和 CCN1 之间的细胞凋亡相互作用： 1. 阐明多个 CCN1 受体如何相互作用； 2. 分析TNFa和CCN1诱导的信号通路如何汇聚； 3. 检查体内 TNFa-CCN1 相互作用的生理意义。我们预计这些研究将产生关于细胞外基质如何调节 TNF 细胞因子活性的重要新信息，并阐明 TNFa 发挥作用的许多疾病过程。