CdK5, OX40, and Immune Tolerance in Uveitis

葡萄膜炎中的 CdK5、OX40 和免疫耐受

• 批准号: 9053492
• 负责人: John James Letterio
• 金额: $ 39.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053492
• 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

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（申请人提供）：葡萄膜炎是一种常见的眼部疾病，反复发作，炎症严重。异常T细胞反应在葡萄膜炎的发病机制中起核心作用。OX40是T细胞激活功能和存活所必需的关键共刺激分子。然而，执行这一关键共刺激信号的关键下游分子仍未完全阐明。我们的总体目标是更好地了解葡萄膜炎的免疫病理机制，并进一步测试诱导免疫耐受治疗眼部炎症的新策略。最近，我们发现OX40在人葡萄膜炎和动物模型中均上调，而阻断OX40信号可减轻眼部炎症。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，CdK5是一种最近与T细胞生物学有关的独特蛋白。此外，阻断CdK5可减轻ox40增强的眼部炎症。基于上述发现，我们假设CdK5是OX40共刺激的关键中介，通过减少T细胞凋亡和/或能量导致葡萄膜炎的加重。为了验证这一假设，我们提出(1)确定OX40和CdK5在实验性葡萄膜炎模型中的表达动力学以及OX40激活对CdK5调控的影响；(2)利用Cre-loxP重组酶系统检测CdK5作为OX40共刺激的关键中介，检测CdK5靶向治疗眼部炎症的疗效；(3)明确CdK5促进OX40在葡萄膜炎中抑制T细胞凋亡和能量的分子机制。