Effects of lipofuscin accumulation on lysosomal functions of human RPE cells

在工业化国家，年龄相关性黄斑变性（AMD）是50岁以上法定失明的主要原因。一些证据表明，视网膜色素上皮（RPE）和布鲁赫膜的老化变化在该疾病的发病机制中起关键作用。在有丝分裂后的RPE细胞中，随着年龄的增长，自荧光脂褐素颗粒主要作为从光感受器外节脱落的膜盘不断吞噬的副产物在溶酶体腔室中积累。最近发现了人RPE脂褐素的主要类视黄醇成分：n -视黄醇- n -视黄醇乙醇胺（A2-E）。在人RPE细胞培养中，我们计划研究A2-E对溶酶体降解功能的影响，并评估其作用机制。具体目的包括确定A2-E对溶酶体酶的抑制机制，其对基底细胞侧吞噬活性的影响以及A2-E积累的地形变化。这些研究不仅是为了更好地理解脂褐素积累的作用，也是为了在实验和治疗目的上操纵这些机制。

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the industrialized world beyond 50 years of age. Several lines of evidence suggest that ageing changes of the retinal pigment epithelium (RPE) and Bruch's membrane play a key role in the pathogenesis of the disease. In postmitotic RPE cells autofluorescent lipofuscin granules accumulate with age in den lysosomal compartment mainly as a byproduct of constant phagocytosis of membranous discs shed from photoreceptor outer segments. Recently a major retinoid component of human RPE lipofuscin has been identified: N-retinylidene-N-retinylethanolamine (A2-E). In human RPE cell cultures we plan to investigate the effect of A2-E on degradative functions of lysosomes, and to evaluate its mechanism of action. Specific aims include determination of the mechanism of lysosomal enzyme inhibition by A2-E, its influence phagocytic activity at the basal cell side as well as topographic variation of A2-E accumulation. These investigations will be performed not only to better understand the role of lipofuscin accumulation but also to manipulate these mechanisms for both experimental and therapeutic ends.