Local dysregulation of the alternative complement pathway in retinal pigment epithelium as a model for age-related macular degeneration

年龄相关性黄斑变性（AMD）是工业化国家老年人视力丧失的最常见原因。早期AMD的最初体征和临床标志是“玻璃疣”，其是布鲁赫膜和视网膜色素上皮（RPE）之间的细胞外沉积物。AMD的病因尚未完全了解，迄今为止，还没有针对早期AMD的循证治疗。因此，阐明其病理生理机制和可能的新的治疗靶点是非常重要的。最近的研究表明，炎症免疫过程，特别是补体系统，是至关重要的AMD的发展。对玻璃疣组成的研究表明，它们含有补体旁路途径的蛋白质。此外，遗传学研究表明AMD与补体系统基因的变体之间存在显著关联。高危基因和AMD病理生理学的确切相互作用仍然没有得到解决。然而，可以假设先天免疫系统的全身和局部变化的相互作用导致眼睛中的局部疾病表现。本项目的目的是通过研究小鼠RPE中替代补体途径主要成分调节异常的后果来分析这些联系。视网膜下注射编码补体和补体调节因子的慢病毒载体后，我们将检查所得表型，从而确定补体相关变化是否导致AMD样表型。

Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly of industrialized countries. The first signs and clinical hallmarks of early AMD are “drusen” which are extracellular deposits between Bruch’s membrane and the retinal pigment epithelium (RPE). The aetiology of AMD is not entirely understood and so far there is no evidence based treatment for early AMD. In this respect, elucidation of pathophysiological mechanism and possible new therapeutic targets is very important. Recent studies suggest that inflammatory immunological processes, particularly the complement system, are crucial for the development of AMD. Studies on the composition of drusen have revealed that they contain proteins of the alternative complement pathway. Furthermore genetic studies have shown a significant association between AMD and variants of complement system genes. The exact interaction of high risk genes and AMD pathophysiology is still unresolved. However, it can be assumed that the interplay from systemic and local changes of the innate immune system leads to local disease manifestation in the eye. The aim of this project is to analyse these links by investigating the consequences of dysregulation of the main components of the alternative complement pathway in the RPE of mice. Following subretinal injection of lentiviral vectors encoding complement and complement regulatory factors we shall examine the resulting phenotype and thus determine whether complement associated changes result in an AMD-like phenotype.