EPITHELIAL AND ENDOTHELIAL PROLIFERATION IN CORN1 MICE

角膜新生血管和角膜表面疾病的分子基础仍然知之甚少。目前可用于研究这些疾病的实验模型往往依赖于外部刺激-创伤，可能无法反映自发性疾病的机制。最近描述的突变体corn 1提供了第一个由遗传决定的自发性角膜上皮疾病和新生血管形成的动物模型。这些动物可以为生化研究和阐明这些过程中涉及的途径提供可重复的组织来源。Corn 1小鼠出现角膜上皮局灶性过度增殖，随后出现新血管形成。这些特征保持不变，不会退化。最终，corn 1小鼠会患上皮质白内障。第二个自发突变的corn 1基因座，corn 1/2 J，在不同的遗传背景，表现出轻度上皮表型，没有新血管形成。拟议研究的总体目标是深入了解corn 1和corn 1/2 J小鼠上皮细胞增殖和新生血管形成之间的关系，评估增殖和血管生成的抑制剂或增强剂的存在或不存在，并确定是否有共同或不同的分子生物学机制调节这些现象。具体而言，在该项目的成功结束时，将通过定位克隆策略确定corn 1和corn 1/2 J的分子基础。此外，通过遗传杂交，将评估新等位基因corn 1/2 J的性质，以确定角膜增殖和新生血管形成的表型表达差异的遗传基础。鉴定相关基因将有助于阐明与这些难治性临床问题相关的分子机制。加强对角膜新生血管和表面疾病导致失明的生物化学和分子生物学机制的理解是更有效地治疗这些相关眼部疾病的第一步。

The molecular basis of corneal neovascularization and corneal surface disease are still poorly understood. Current experimental models available for the study of these diseases often rely on external stimuli-trauma that may not reflect the mechanisms of spontaneous disease. A recently described mutant, corn1, provides the first animal model of genetically determined, spontaneous corneal epithelial disease and neovascularization. These animals can provide a reproducible source of tissue for biochemical studies and for elucidation of the pathways involved in these processes. Corn1 mouse develops focal hyper-proliferation of the corneal epithelium, followed by neovascularization. These features remain constant and do not regress. Eventually, corn1 mice develop cortical cataracts. A second spontaneous mutation in the corn1 locus, corn1/2J, on a different genetic background, demonstrates a mild epithelial phenotype, with no neovascularization. The overall goal of the proposed research is to gain insights into the relationship between epithelial proliferation and neovascularization in corn1 and corn1/2J mice, to assess the presence or absence of suppressors or enhancers of proliferation and angiogenesis, and to determine if there are common or different molecular biological mechanisms regulating these phenomena. Specifically, at the successful conclusion of this project, the molecular basis of corn1 and corn1/2J will be identified through a positional cloning strategy. In addition, through genetic cross, the nature of a new allele, corn1/2J, will be evaluated to determine the genetic basis for the difference in phenotypic expression of the corneal proliferation and neovascularization. Identification of the responsible gene(s) will help clarify molecular mechanisms relating to these refractory clinical problems. Enhanced understanding of the biochemical and molecular biological mechanisms responsible for blindness caused by corneal neovascularization and surface disease is the first step towards more effective treatment of these related ocular diseases.