Despite remarkable progress in uncovering the molecular defects in inherited retinal degenerations and retinoblastoma, the pathogenesis of these conditions remains unclear. The same or similar mutations of photoreceptor genes can generate diverse clinical disorders, ranging from autosomal dominant retinitis pigmentosa (RP) to macular degeneration to sector RP. Similar retinal degenerations in rd and rds mice and RCS (rdy) rats have been shown to proceed by an apoptotic pathway. In addition, transgenic mice which express the human papillomavirus E7 protein (which inactivates the retinoblastoma protein) specifically in photoreceptor cells develop apoptotic retinal degeneration rather than retinoblastoma. The retinal degeneration in this model was shown to be dependent upon the presence of a functional p53 gene. These and other recent results suggest there may be overlap in the molecular pathways regulating cell survival and proliferation. Therefore, the purpose of the proposed research is to investigate the molecular pathways leading to retinal degeneration or retinoblastoma in the various mouse models. Several genes which either inhibit apoptosis (bcl-2 and bcl-XL) or promote apoptosis (bax and bcl-Xs) have recently been identified. The ability of bcl-2 and bcl-XL to block apoptotic retinal degeneration in rd and rds mice and in transgenic mice expressing E7 in the retina will be tested by producing transgenic mice expressing either the bcl-2 or bcl-XL gene under the control of the interstitial retinol-binding protein (IRBP) promoter and interbreeding these mice to the various retinal degeneration mice. The rd and rds mice will also be interbred to mice lacking a functional p53 gene to determine the dependence of apoptosis in those models upon p53. Similarly, mice expressing the SV40 T-Antigen oncogene under the control of the IRBP promoter and which develop retinoblastoma will be interbred with mice expressing IRBP-bax or IRBP-bcl-XS to determine whether these genes can suppress tumorigenesis. These studies will provide answers to several important questions: (1) Do phenotypically distinct retinal degeneration syndromes induced by different mutations (rd vs rds) result from a common pathway to apoptosis? (2) Does the apoptotic pathway(s) triggered by mutation of photoreceptor-specific genes share common elements with the pathway triggered by disruption of cell cycle control? (3) Are bcl-2 and bax functionally equivalent in photoreceptor cells? (4) Can tumorigenesis be blocked by the overexpression of genes that promote apoptosis? Ultimately, results from these studies may lead to novel therapeutic approaches for treatment of both of disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY010992-01
Application #
2165208
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-05-01
Project End
2000-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Ctrc Research Foundation
Department
Type
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Hopp, R M; Ransom, N; Hilsenbeck, S G et al. (1998) Apoptosis in the murine rd1 retinal degeneration is predominantly p53-independent. Mol Vis 4:5
Ma, C; Papermaster, D; Cepko, C L (1998) A unique pattern of photoreceptor degeneration in cyclin D1 mutant mice. Proc Natl Acad Sci U S A 95:9938-43