Molecular mechanisms of phagosome maturation and degradation in the retinal pigment epithelium in health and disease

健康和疾病状态下视网膜色素上皮吞噬体成熟和降解的分子机制

• 批准号: G0700778/1
• 负责人: Miguel Seabra
• 金额: $ 52.04万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700778%2F1
• 关键词: Molecular; mechanisms; phagosome; maturation; degradation

The retinal pigment epithelium (RPE) is a single cell layer in the eye that lies immediately beneath the photoreceptors, the cells that detect light. Photoreceptors must undergo a process of daily partial renewal in order to function properly. Everyday at about the onset of daylight, photoreceptors shed their tips, which are engulfed (phagocytosed) by the RPE and degraded. RPE cells do not normally divide in the adult so a single RPE cell phagocytoses and degrades an enormous amount of photoreceptor material during a 70 year lifespan. This prodigious activity takes its toll and as the RPE ages undigested products of phagocytosis accumulate within the cells and this is believed to contribute to the accumulation of debris with age, particularly in people suffering from age-related macular degeneration, the leading cause of blindness in the Western world. Whilst considerable progress has recently been made in identifying the molecules that regulate the initial engulfment process, much less is known about what regulates the subsequent degradation of the vacuole containing the phagocytosed material (the phagosome). In cells where phagosome degradation has been better characterised the phagosome has been shown to undergo a maturation process involving the sequential acquisition of specific proteins that are necessary for the phagosome to gain the ability to fuse with the lysosome. Within the lysosome enzymes degrade the phagosome. Using high resolution microscopic methods we will identify the transport steps required for phagocytosed photoreceptor outer segments to be delivered to the lysosome and degraded. We will then determine which molecules regulate phagosome maturation and degradation in RPE cells, focussing on Rab proteins and motor proteins, some of which we have already shown are present in RPE cells and regulate other transport steps within the cell. This study will identify mechanisms whereby a process that is essential to human vision takes place and will help us to understand how this process breaks down with age and in eye disease.

视网膜色素上皮(RPE)是眼睛中的一个单细胞层，位于感光细胞的正下方，光感受器是探测光线的细胞。光感受器必须经历一个每日部分更新的过程才能正常发挥作用。每天黎明时分，光感受器的尖端脱落，被RPE吞噬并降解。成人的RPE细胞通常不会分裂，因此单个RPE细胞在70年的寿命中吞噬并降解大量的光感受器物质。这种巨大的活动造成了损失，随着RPE年龄的增长，吞噬作用的未消化产物在细胞内积累，这被认为是随着年龄的增长而导致碎片积累的原因，特别是在患有老年性黄斑变性的人中，这是西方世界的主要失明原因。虽然最近在确定调节最初吞噬过程的分子方面取得了相当大的进展，但关于是什么调节含有吞噬物质(吞噬小体)的液泡随后的降解还知之甚少。在吞噬小体降解得到更好描述的细胞中，吞噬小体已经被证明经历了一个成熟的过程，涉及到吞噬小体获得与溶酶体融合的能力所必需的特定蛋白质的顺序获取。在溶酶体内，酶会降解吞噬小体。使用高分辨率显微镜方法，我们将确定吞噬的光感受器外段被运送到溶酶体并被降解所需的运输步骤。然后，我们将确定哪些分子调节RPE细胞中吞噬小体的成熟和降解，重点关注Rab蛋白和马达蛋白，我们已经证明其中一些存在于RPE细胞中，并调节细胞内的其他运输步骤。这项研究将确定对人类视觉至关重要的过程发生的机制，并将帮助我们理解这一过程是如何随着年龄和眼病而分解的。