CdK5, OX40, and Immune Tolerance in Uveitis

描述（由申请人提供）：葡萄膜炎是一种常见的眼部疾病，具有复发性和严重的炎症。异常的T细胞反应在葡萄膜炎的发病机制中起核心作用。OX 40是T细胞活化功能和存活所必需的关键共刺激分子。然而，关键的下游分子执行这一关键的共刺激信号仍有待充分阐明。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，我们已经表明，OX 40在人类葡萄膜炎和动物模型中上调，而阻断OX 40信号转导减弱眼部炎症。此外，我们的初步研究表明，OX 40信号转导影响细胞周期蛋白依赖性激酶5（CdK 5）的表达，这是一种独特的蛋白质，最近被牵连在T细胞生物学。此外，阻断CdK 5可减弱OX 40增强的眼部炎症。基于上述发现，我们假设CdK 5是0X 40共刺激的关键中介，通过减少T细胞凋亡和/或无反应性导致加重的葡萄膜炎。为了验证这一假设，我们提出：（1）确定OX 40和CdK 5在实验性葡萄膜炎模型中的表达动力学以及OX 40活化对CdK 5调节的影响;（2）使用Cre-loxP重组酶系统测试CdK 5作为OX 40共刺激的关键中介，并检查CdK 5靶向治疗眼部炎症的疗效;（3）阐明CdK 5促进OX 40抑制T细胞凋亡和抑制葡萄膜炎中T细胞无能的分子机制。

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.