Animal Model for a Hereditary Macular Degeneration

描述(申请人提供)：老年性黄斑变性(AMD)和 其新生血管并发症导致永久丧失中心视力和合法视力。 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因缺乏相关的 动物模型。然而，最近，组织中至少有六个突变 金属蛋白酶抑制因子-3编码基因(TIMP-3)在 索尔斯比眼底营养不良(SFD)患者(1-3) 与新生血管性AMD相似(4)。转基因小鼠其中一种 突变Y172C被产生，并被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 在SFD。这些TIMP-3/172小鼠将为深入了解TIMP-3/172的发病机制提供依据。 以及一种测试黄斑变性潜在治疗方法的手段。这 一项提案旨在勾勒出导致疾病的致病机制 TIMP-3/172小鼠和它们的人类同行。刻画人物形象 这种疾病的致病基础可能为治疗方法提供参考 治疗自发性黄斑变性和其他形式的黄斑变性。该项目将有3个 组成部分：首先将评估TIMP-3/172的效果 突变对TIMP-3功能和血管生成的影响。第二个将是识别 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 在TIMP-3转基因小鼠中将进行评估并与 未受影响的细胞。这些研究旨在揭示特定的生物途径。 与此动物模型中的病理相关。任何这样的路径都可能 未来可能会被操纵以减缓/预防疾病的进程。

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.