Animal Model for a Hereditary Macular Degeneration

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）和 其新生血管并发症导致永久性中央视力丧失法律的 失明目前还没有治愈黄斑变性的方法。治疗 AMD及其新生血管并发症由于缺乏相关的 动物模型然而，最近，组织中至少有六个突变， 金属蛋白酶抑制剂-3编码基因（TIMP-3）在 Sorsby眼底营养不良（SFD）患者（1-3）， 与新生血管性AMD相似（4）。转基因小鼠 突变，Y172 C，产生并发现具有视网膜病理 最终导致视网膜变性和视网膜下新生血管形成，如发现的 在SFD。这些TIMP-3/172小鼠将提供对肿瘤的发病机制的见解。 以及测试黄斑变性的潜在治疗方法的手段。这 该提案旨在描述占疾病的致病机制， TIMP-3/172小鼠及其人类对应物。表征 这种疾病的致病基础可以建议治疗方法， 治疗SFD和其他形式的黄斑变性。该项目将有3 组分：首先将评估TIMP-3/172的作用， 突变对TIMP-3功能和血管生成的影响。第二个将是确定 改变突变型TIMP-3疾病进展的遗传变量 转基因小鼠最后，患病视网膜细胞的基因表达模式 将评估TIMP-3转基因小鼠中的TIMP-3表达，并与 不受影响的细胞这些研究旨在揭示特定的生物学途径 与该动物模型中的病理学相关。任何这样的途径都可能 在将来可能被操纵以减缓/预防疾病过程。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) and its neovascular complications cause permanent loss of central vision and legal blindness. There is currently no cure for macular degeneration. Treatment for AMD and its neovascular complications has been hampered by a lack of relevant animal models. Recently, however, at least half a dozen mutations in the Tissue Inhibitor of Metalloproteinases-3-encoding gene (TIMP-3) were identified in patients with Sorsby's fundus dystrophy (SFD) (1-3), a disease with similarities to neovascular AMD (4). Mice transgenic for one of these mutations, Y172C, were generated and found to possess retinal pathology culminating in retinal degeneration and subretinal neovascularization, as found in SFD. These TIMP-3/172 mice will provide insights into the pathogenesis of and a means to test potential treatments for macular degeneration. This proposal aims to delineate pathogenic mechanisms accounting for disease in the TIMP-3/172 mice and their human counterparts. Characterization of the pathogenic basis of this disease could suggest therapeutic approaches for treating SFD and other forms of macular degeneration. The project will have 3 components: The first will be to evaluate the effects of the TIMP-3/172 mutation on TIMP-3 function and on angiogenesis. The second will be to identify genetic variables that modify disease progression in the mutant TIMP-3 transgenic mice. Finally, patterns of gene expression in diseased retinal cells in the TIMP-3 transgenic mice will be evaluated and compared with those in unaffected cells. These studies aim to reveal specific biological pathways relevant to the pathology in this animal model. Any such pathways could potentially be manipulated in the future to slow/prevent the disease process.