The Role of Muller Cells in Visual Pigment Regeneration

描述(申请人提供)：光感知的第一个事件是由视网膜感光细胞内的视蛋白视觉色素捕获光子。这会引发视黄醛发色团的化学变化，视黄醛发色团是一种与每种视蛋白色素中含有的维生素A相关的小分子。这可以比作绊倒捕鼠器。在将光敏感度恢复到“漂白”的色素之前，视黄醛发色团必须经过化学再生，即必须重新设置捕鼠器。这是通过视网膜色素上皮(RPE)中的多步酶途径实现的，RPE是与视网膜相邻的一层细胞。这种酶途径中几乎每一种蛋白质的基因突变都会导致某种类型的遗传性失明疾病。这表明“视觉周期”对人类视觉的重要性。多年来，越来越多的证据表明，位于视网膜内的另一种细胞--穆勒细胞也参与了视觉生色团的再生。具体地说，米勒细胞可能有助于锥状光感受器中生色团的再生。视锥细胞在明亮的光线下提供高分辨率的色觉，对人类的正常视力至关重要。关于穆勒细胞如何再生视觉生色团，以及RPE与穆勒细胞在杆状优势物种(如人类)中的相对贡献，我们几乎一无所知。目前的申请采用“双管齐下”的办法解决这些问题。一组实验试图确定在视网膜匀浆中检测到的负责维生素A加工活动的每一种蛋白质。另一组实验试图确定之前在米勒细胞中发现的每一种维生素A加工蛋白的功能。来自这些方法的信息应该会聚在一起，以得出关于穆勒细胞在视觉色素再生中所起作用的清晰图景。与公共健康相关：光感知由眼睛中的视觉色素调节。为了保持视力，这些色素必须不断再生。本课题旨在研究视觉色素再生的生化机制。色素再生缺陷会导致遗传性致盲疾病。该项目将帮助我们了解这些遗传病是如何产生的。

DESCRIPTION (provided by applicant): The first event in light perception is capture of a photon by an opsin visual-pigment within a photoreceptor cell of the retina. This triggers a chemical change in the retinaldehyde chromophore, a small molecule related to vitamin A contained within each opsin pigment. This can be likened to the tripping a mouse trap. Before light sensitivity can be restored to the `bleached' pigment, the retinaldehyde chromophore must be chemically regenerated, i.e., the mouse trap must be reset. This is accomplished by a multi-step enzyme pathway in the retinal pigment epithelium (RPE), a layer of cells adjacent to the retina. Mutations in the gene for almost every protein within this enzyme pathway cause some type of inherited blinding disease. This indicates the importance of the `visual cycle' to vision in humans. Over the years, evidence has accumulated that another type of cell, the Muller cell, located within the retina, also participates in the regeneration of visual chromophore. In particular, Muller cells may assist in the regeneration of chromophore destined for cone photoreceptors. Cones provide high-resolution color vision in bright light, and are critical to normal sight in humans. Almost nothing is known about how Muller cells regenerate visual chromophore, and what are the relative contributions of RPE versus Muller cells in rod-dominant species, such as humans. The current application addresses these questions using a `two-pronged' approach. One set of experiments seeks to identify each protein responsible for the vitamin A-processing activities detected in retina homogenates. Another set of experiments seeks to define the function of each vitamin A-processing protein previously identified in Muller cells. Information from these approaches should converge to yield a clear picture about the role of Muller cells in visual-pigment regeneration. PUBLIC HEALTH RELEVANCE: Light perception is mediated by visual pigments in the eye. For sustained vision, these pigments must be continuously regenerated. This project is to study the biochemical mechanisms of visual-pigment regeneration. Defects in pigment regeneration cause inherited blinding diseases. The project will help us understand how these genetic diseases arise.