Angiogenesis, the formation of new blood vessels, is a tightly regulated function determined by the local balance of endogenous angiogenesis stimulators versus inhibitors. The central hypothesis for this proposal is that the angiogenic balance varies between individuals and that this variation is in large part genetically determined. Indeed, epidemiological data suggests that different racial populations have varied susceptibility to ocular neovascularization. We have surveyed inbred mouse strains to see if mice have a range of angiogenic diversity that models that of humans. Surprisingly, we found a large range of angiogenic responses to pellets of basic fibroblast growth factor (bFGF) implanted in the corneas of different strains. The difference between the lowest response and the highest response was 1200 percent. To date, the most sensitive strain is an albino mouse known as 129. In this strain, corneal bFGF pellets induce very aggressive corneal and iris neovascularization as compared to C57 black mice which have moderate corneal angiogenesis and no iris neovascularization. Interestingly, tyrosinase positive substrains of 129 mice (which are pigmented), retain the overly aggressive corneal neovascular response but do not have iris neovascularization. To evaluate the aggressive corneal angiogenic response of the 129 mice we propose to breed them with other inbred strains with lower responses. We will then characterize the angiogenic phenotype of the offspring of the crosses and will use genetic mapping to identify the chromosomal locus that segregates with this phenotype. If there are candidate genes in the region, these will be screened for alterations in DNA sequence. The goal of this proposal is to characterize the angiogenic phenotypes of different murine inbred strains and to identify the genetic contributions to these phenotypes. Identifying the genes controlling ocular angiogenesis in mice will help find similar genes in humans, the characterization of which may suggest new therapies for pathologic neovascularization seen in neovascular glaucoma and macular degeneration.
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