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.

Public Health Relevance

T cell-mediated uveitis is a major cause of visual loss and significant economic as well as health-related burdens. Through studying the role of T cell co-stimulation and CdK5 in immune tolerance, this application will enable us to better understand the mechanism of uveitis, and pinpoint novel potential therapeutic targets. Therefore, this project is significant and will contribute to the health and welfare of our society.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022937-01
Application #
8419629
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$413,539
Indirect Cost
$147,579
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106