CdK5, OX40, and Immune Tolerance in Uveitis

葡萄膜炎中的 CdK5、OX40 和免疫耐受

基本信息

批准号：
8812858
负责人：
John James Letterio
金额：
$ 39.22万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812858
关键词：
Ablation Adoptive Transfer Affect Animal Model Antigens Apoptosis Attenuated BCL2 gene Blindness Blocking Antibodies CD4 Positive T Lymphocytes Cells Cellular biology Cyclin-Dependent Kinase 5 Disease Economics Eye Eye diseases Funding Goals Health Human Immune Tolerance Induction of Apoptosis Infiltration Inflammation Inflammatory Kinetics Knockout Mice Lead Lymphocyte Mediating Modeling Molecular Mus Ovalbumin Pathogenesis Play Population Protein-Serine-Threonine Kinases Proteins Recombinants Regulation Relapse Reporting Role Severities Signal Transduction Social Welfare Societies Spleen Staging System T cell anergy T cell response T-Cell Activation T-Lymphocyte TNFSF4 gene Testing Therapeutic Transfection Treatment Efficacy Uveitis Wild Type Mouse anergy autoimmune uveitis base cytokine inhibitor/antagonist lymph nodes novel novel strategies olomoucine prevent promoter recombinase roscovitine therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Uveitis is a common eye disorder with relapsing and serious inflammation. Aberrant T cell response plays a central role in the pathogenesis of uveitis. OX40 is a key co-stimulatory molecule essential for T cell activation function and survival. However, the key downstream molecules executing this critical co-stimulation signal remain to be fully elucidated. Our overall goal is to better understand the immunopathological mechanism of uveitis and further test the novel strategy of inducing immune tolerance for the treatment of ocular inflammation. Recently, we have shown that OX40 is up-regulated in both human uveitis and animal models, whereas blocking OX40 signaling attenuates ocular inflammation. In addition, our preliminary study suggests that OX40 signaling influences the expression of cyclin-dependent kinase 5 (CdK5), a unique protein that has been recently implicated in T cell biology. Furthermore, blocking CdK5 attenuates OX40-enhanced ocular inflammation. Based on above findings, we postulate that CdK5 is a critical intermediary of OX40 co- stimulation, leading to exaggerated uveitis by reducing T cell apoptosis and/or anergy. To test this hypothesis, we propose (1) to determine the expression kinetics of OX40 and CdK5 in experimental uveitis models and the impact of OX40 activation on CdK5 regulation; (2) to test CdK5 as a key intermediary of OX40 co-stimulation using Cre-loxP recombinase system and examine the therapeutic efficacy of CdK5-targeting treatment for ocular inflammation; (3) to define the molecular mechanism by which CdK5 facilitates OX40 action in preventing T cell apoptosis and anergy in uveitis.

描述（由申请人提供）：葡萄膜炎是一种常见的眼睛疾病，具有复发和严重的炎症。异常T细胞反应在葡萄膜炎的发病机理中起着核心作用。 OX40是T细胞激活功能和存活所必需的关键共刺激分子。但是，执行此临界共同刺激信号的钥匙下游分子仍尚待完全阐明。我们的总体目标是更好地了解葡萄膜炎的免疫病理学机制，并进一步测试诱导眼部炎症治疗免疫耐受性的新策略。最近，我们表明OX40在人葡萄膜炎和动物模型中都被上调，而阻断OX40信号传导会减轻眼部炎症。此外，我们的初步研究表明，OX40信号传导影响细胞周期蛋白依赖性激酶5（CDK5）的表达，这是一种最近与T细胞生物学有关的独特蛋白质。此外，阻塞CDK5会减轻OX40增强的眼部炎症。根据上述发现，我们假设CDK5是OX40共同刺激的关键中介，通过减少T细胞凋亡和/或厌食来导致夸张的葡萄膜炎。为了检验该假设，我们建议（1）在实验性葡萄膜炎模型中确定OX40和CDK5的表达动力学以及OX40激活对CDK5调控的影响；（2）使用CRE-LoxP重组酶系统测试CDK5作为OX40共刺激的关键中介，并检查CDK5靶向治疗的眼部炎症的治疗疗效；（3）定义CDK5促进OX40在防止T细胞凋亡和葡萄膜炎厌食的作用的分子机制。