GENETIC STUDIES OF OCULAR ANGIOGENESIS

血管生成，即新血管的形成，是一种受到严格调控的功能，由内源性血管生成刺激剂与抑制剂的局部平衡决定。该提议的中心假设是，血管生成平衡在个体之间是不同的，这种差异在很大程度上是由遗传决定的。事实上，流行病学数据表明，不同种族的人群对眼部新生血管的易感性各不相同。我们调查了近亲繁殖的小鼠品系，看看小鼠是否具有模仿人类血管生成多样性的范围。令人惊讶的是，我们发现碱性成纤维细胞生长因子（bFGF）颗粒植入不同菌株的角膜后，血管生成反应范围很大。最低反应和最高反应之间的差距是1200%。迄今为止，最敏感的菌株是一种名为129的白化小鼠。在该菌株中，角膜bFGF颗粒诱导了非常积极的角膜和虹膜新生血管形成，而C57黑小鼠的角膜血管生成适中，虹膜新生血管没有形成。有趣的是，129只小鼠的酪氨酸酶阳性亚株（着色）保留了过度侵袭性的角膜新生血管反应，但没有虹膜新生血管形成。为了评估这129只小鼠的侵袭性角膜血管生成反应，我们建议将它们与其他反应较低的近交系杂交。然后，我们将表征杂交后代的血管生成表型，并将使用遗传作图来确定与该表型分离的染色体位点。如果在该区域有候选基因，这些基因将被筛选DNA序列的改变。本提案的目的是表征不同小鼠近交系的血管生成表型，并确定这些表型的遗传贡献。确定控制小鼠眼部血管生成的基因将有助于在人类中找到类似的基因，其特征可能为新血管性青光眼和黄斑变性的病理性新生血管提供新的治疗方法。

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.