While abnormal angiogenesis is implicated in the pathology of over 20 eye diseases in humans and as such, is the leading cause of blindness, the underlying pathological mechanisms are not fully understood. The applicant's preliminary results show that C57BL/6Trp53tm1Tyj homozygous null mutants (B6 p53-/-) exhibit hypoplastic optic nerves, abnormal vitreal neovascularization and fibroplasia, and retinal dysplasia, while heterozygous and wild-type littermates do not. These phenotypic characteristics of B6 p53-/- mice are similar to those observed in familial vitreoretinopathy, retinopathy of prematurity, and persistent hyperplastic primary vitreous and, therefore, may provide an excellent animal model for these human ocular diseases in which abnormal vascularization is observed. This model will also provide a means for elucidating the underlying mechanisms through which p53 functions to mediate the ocular abnormalities observed. 129/Sv mice carrying the same p53 null mutation as B6 mice do not exhibit any of the ocular disorders described for B6. This strain difference in phenotypic expression provides the unique opportunity to carry out genetic studies to identify factors that are acting in vivo in concert with the loss of p53 activity. This is extremely important because unlike previous p53 studies done in vitro, this study will allow not only for the identification of gene products which influence p53 function, but will also test the true physiological importance of these factors. Finally, while the eye will be used as a model system to study the role of p53 in optic nerve development and abnormal angiogenesis, the information gained concerning the role of p53 in the eye may lead to a better understanding of the overall in vivo function of p53 both in development and tumor suppression in the entire organism. In this application, the role of p53 in eye development and pathogenesis will be elucidated by determining (a) the spatial and temporal expression pattern of p53 during embryogenesis and postnatal development, and the developmental disruption that leads to (b) the hypoplastic optic nerve and (c) vitreal neovascularization in B6 p53-/- but not 129/Sv p53-/- mice. In addition, the chromosomal location of the genes which lead to the ocular abnormalities in B6 p53-/- but not 129/Sv p53-/- mice will be identified.
| Haider, Neena B; Ikeda, Akihiro; Naggert, Jurgen K et al. (2002) Genetic modifiers of vision and hearing. Hum Mol Genet 11:1195-206 |
| Kameya, Shuhei; Hawes, Norman L; Chang, Bo et al. (2002) Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Hum Mol Genet 11:1879-86 |
