Signal Transduction Pathways In The Eye Of Transgenic Mi

National Eye Institute

Investigators

Abstract

In collaborative studies with Dr. Charles Egwuagu (Laboratory of Immunology, NEI) we have been studying the JAK/STAT signaling pathway in the lens. This collaboration resulted in the development of transgenic mice and rats with constitutive expression of gamma interferon in their eyes, which became useful animal models for the study of experimental autoimmune uveitis and anterior uveitis. This ongoing collaboration allowed us to study how constitutive expression of gamma interferon and its induction and activation of gamma interferon-inducible transcription factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression.We found that the expression of the members of the interferon regulatory factors (IRFs) family of transcription factors is not only activated in the gamma interferon transgenic mice, but it is also expressed in the normal lens. Our data indicates that expression of IRF transcription factors is spatially regulated in the lens and that distinct IRFs may contribute to differential gene regulation in the epithelia and fiber compartment of the lens. These findings have important implications for understanding signal transduction pathways in the lens. In another collaboration with Dr. Charles Egwuagu we developed double transgenic mice expressing gamma interferon and the oncogenic SV40 large T antigen in the lens. Our results showed that in the double transgenic mice, there is a progressive regression of the lens tumor, resulting in complete tumor regression in the adult double transgenic mice. We showed that the anti-tumor effects are not mediated by immunological effector cells. Instead, the rescue of the neoplastic phenotype is mediated in part by enhanced expression of the IFN gamma-inducible tumor suppressors IRF-1 and ICSBP, activation of caspase-1 (or ICE, interleukin-1b-converting enzyme) and IFN gamma-dependent apoptosis. These double transgenic mice are useful animal models for the study of the possible clinical uses of IRFs for tumor regression therapy.