ANIMAL MODELS FOR A HEREDITARY MACULAR DEGENERATON

描述(摘自申请者的摘要)：视网膜变性 疾病可以根据关节的解剖位置大致分类。 临床表现异常。疾病组的退行性变 我们所知的视网膜色素变性通常发生在外周到中央 渐变。相反，黄斑变性的影响，正如它的名字 表示视网膜的中央区域。黄斑变性导致 中心视力、色觉、对比敏感度和精细视觉丧失 歧视。目前还没有治愈黄斑变性的方法。 老年性黄斑变性及其新生血管的治疗 由于缺乏相关的黄斑动物模型，并发症受到阻碍。 变性或黄斑营养不良。基因鉴定的研究进展 导致黄斑变性的基因识别滞后于导致黄斑变性的基因 视网膜色素变性。然而，最近有六种以上的基因突变 Sorsby病患者TIMP-3编码基因(TIMP-3)的检测 眼底营养不良(SFD)。SFD是一种退行性疾病，影响 特别严重的斑疹。随着基因缺陷的识别 导致黄斑变性，就有可能产生动物 模型(S)，并用这些来定义分子机制 这导致了病原学的发现。申请者最近 鉴定了人TIMP-3启动子区域。用它来驱动变异的 人TIMP-3基因的不同版本，转基因突变人TIMP-3的小鼠 已经产生了。这些老鼠似乎有几种异常。 在SFD患者中观察到的，包括相对较厚的视网膜下层 色素上皮(RPE)在整个视网膜上沉积，并在 布鲁赫膜，随着时间的推移大小不断扩大。转基因对照小鼠 对于野生型人类，TIMP-3具有正常的视网膜。在这里提出的这项研究 目的是进一步鉴定这些转基因突变TIMP-3小鼠的特征。在……里面 此外，使用Cre/lox重组系统，增加了小鼠品系 将生成包含特定于RPE或全局TIMP-3的敲除基因。这个 在每个基因改变的品系中观察到的致病机制 将对老鼠(以及从它们杂交而来的线条)进行评估。这个 SFD的致病基础的特征可以提示治疗 治疗这种疾病和其他形式的黄斑病变的方法 退化。

DESCRIPTION (Adapted from applicant's abstract): Retinal degenerative diseases can be broadly categorized by the anatomical location of the clinically manifested abnormalities. Degeneration in the group of diseases known as retinitis pigmentosa typically proceeds in a peripheral to central gradient. Macular degeneration, in contrast, affects, as the name indicates, the central region of the retina. Macular degeneration causes a loss in central vision, color vision, contrast sensitivity and fine visual discrimination. There is currently no cure for macular degeneration. Treatment for age-related macular degeneration (AMD) and its neovascular complications is hampered by a lack of relevant animal models for macular degeneration or macular dystrophies. Progress in identification of genes causing macular degeneration lags behind that in identifying genes causing retinitis pigmentosa. Recently, however, over six mutations have been detected in the TIMP-3-encoding gene (TIMP-3) in patients with Sorsby's fundus dystrophy (SFD). SFD is a degenerative disease that affects the macula with particular severity. With the identification of a gene defect causing macular degeneration, it becomes possible to generate (an) animal model(s) of the disease and to use these to define the molecular mechanisms which lead to the pathogenic findings. The applicants have recently identified the human TIMP-3 promoter region. Using this to drive mutated versions of a human TIMP-3 cDNA, mice transgenic for mutant human TIMP-3 have been generated. These mice appear to possess several abnormalities observed in SFD patients, including a relatively thick layer of sub-retinal pigment epithelium (RPE) deposits across the entire retina and defects in Bruch's membrane which expand in size over time. Control mice transgenic for wild-type human TIMP-3 have normal retinas. The research proposed here aims to further characterize these transgenic mutant TIMP-3 mice. In addition, using the Cre/lox recombination system, additional lines of mice containing RPE-specific or global TIMP-3 knock-outs will be generated. The pathogenic mechanisms observed in each of the lines of genetically altered mice (and in lines derived from crossing them) will be assessed. The characterization of the pathogenic basis of SFD could suggest therapeutic approaches for treating this disease and other forms of macular degeneration.