Proliferative vitreoretinopathy (PVR), the leading cause of rhegmatogenous retinal detachment (RRD) surgical failure, is a potentially blinding disease. The long-term project goal is to understand how cytokines trigger and perpetuate PVR. This information will lead to more effective treatment strategies designed to prevent or inhibit this condition, and will help to explain why some patients develop progressive disease while others do not. Based on data from the current funding period, the following hypotheses have been developed: The transcription factor NF-kappaB is a key regulator of cytokine expression in retinal pigment epithelial (RPE) cells, and inhibits RPE apoptosis. Cytokine-mediated, cell density-dependent activation of NF-kappaB in RPE cells promotes and perpetuates PVR. Contemporary cell and molecular biological techniques will be employed to address the following Specific Aims: I) To determine whether RPE cell density regulates interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha)-mediated NF-kappaB activation. The effect of cell density on IL-1 and TNF receptor number and receptor-activated NF-kappaB activity will be quantified in cultured human RPE cells. II) To determine whether specific factors relevant to PVR or its treatment downregulate cytokine-activated NF-kappaB in RPE cells. The effect of transforming growth factor beta2 (TGF-beta2) and subretinal fluid from patients with RRD, on RPE cell NF-kappaB activation will be determined. III) To determine whether NF-kappaB regulates RPE cell apoptosis. Density-dependent effects of IL-1, TNFalpha, and specific NF-kappaB inhibitors on NF-kappaB-mediated RPE apoptosis will be quantified. IV) To determine whether specific in vivo NF-kappaB blockade inhibits PVR.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY009106-10A2S1
Application #
6660656
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Dudley, Peter A
Project Start
1992-01-01
Project End
2003-07-31
Budget Start
2002-09-30
Budget End
2003-07-31
Support Year
10
Fiscal Year
2002
Total Cost
$70,825
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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