Effects of lipofuscin accumulation on lysosomal functions of human RPE cells

脂褐质积累对人RPE细胞溶酶体功能的影响

• 批准号: 5244490
• 负责人: Professor Dr. Jürgen Kopitz
• 金额: --
• 依托单位: Universitäts-Augenklinik Bonn
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5244490?language=en
• 关键词: Effects; lipofuscin; accumulation; lysosomal; functions

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.

视网膜相关性黄斑变性（AMD）是工业化世界中50岁以上法律的失明的主要原因。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疾病的发病机制中起着关键作用。在有丝分裂后的RPE细胞中，自发荧光脂褐素颗粒随着年龄的增长而在den溶酶体隔室中积累，主要是作为从光感受器外节脱落的膜盘的恒定吞噬作用的副产品。最近已经鉴定了人RPE脂褐素的主要类视色素组分：N-亚视黄基-N-视黄乙醇胺（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。具体目标包括确定A2-E抑制溶酶体酶的机制，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。这些调查将进行不仅更好地了解脂褐素积累的作用，而且还操纵这些机制的实验和治疗目的。