Inflammatory corneal neovascularization results iil devastating impairment of visual function. Previous studies have provided insights into the multistep process of angiogenesis. However, the signal transduction pathway involved in mediating inflammatory corneal neovascularization remains to be established. Preliminary studies have implicated the proinflammatory cytokines TNF-alpha and IL-1 in inflammatory neovascularization. The pleiotropic, inducible transcription factor NF-kB is acitivated by, and stimulates production of TNF-alpha and IL-1, and plays a pivotal regulatory role in immune and inflammatory responses. NF-kB is a heterodimer consisting of pSO and RelA subunits. The latent form of NF-kB is sequestered in the cytoplasm by IkB-alpha inhibitory proteins. Stimulus induced phosphorylation of IkB-alpha results in rapid degradation of the inhibitor and the release of NF-kB heterodimer which trans locates to nucleus and induces expression of proinflammatory mediators. The duration of the nuclear NF-kB response is regulated by reversible acetylation of the RelA subunit. The Mentored Clinical Scientist Career Development Award proposal will investigate the hypothesis that NF-kB signalining plays a pivotal role in corneal neovascularization.
The specific aims i nclude: 1) analysis of the kinetics and in situ localization of NF-kB activation in response to stimulus induced inflammatory neovascularization; 2) determination of the signaling mechanisms initiating and sustaining inflammatory corneal neovascularization; and 3) characterization of the effects of specific inhibitors and a gene therapy strategy on NF-kB mediated inflammatory corneal neovascularization. The proposed studies should offer insights into the signaling pathway associated with inflammatory corneal neovascularization, and provide novel targets for therapeutic intervention in human corneal diseases.
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