Molecular Mechanisms of Retinal Degeneration and the visual cycle in Drosophila

描述（由申请人提供）：光检测由G蛋白偶联受体（称为视紫红质）的光活化启动。这种色素由一种称为视蛋白的蛋白质成分和一种称为发色团的维生素A衍生物组成。发色团是色素的光敏部分，其对光响应而经历顺反异构化。在哺乳动物的视杆细胞和视锥细胞中，发色团必须通过酶途径再生，称为视觉循环。这个周期的缺陷会导致各种影响眼睛的退行性疾病。在果蝇和人类内在光敏视网膜神经节细胞（ipRGC）中，认为发色团在光刺激后仍与视蛋白相关，并且发色团似乎仅通过暴露于第二光子的光而再生。因此，人们认为这些色素不依赖于视觉周期。令人惊讶的是，最近发现苍蝇也存在类似的视觉周期。这打开了使用苍蝇作为模型生物体的可能性，在其中研究视觉周期和视网膜变性，其中断的结果。该项目的一个目标是进一步了解果蝇视觉周期扰动导致视网膜变性的基础。这将通过研究突变破坏在视觉周期中发挥作用的基因的影响来实现，使用生物化学，细胞生物学和遗传学方法的组合。该项目的第二个目标是使用遗传和生物化学方法来测试新制定的果蝇视觉周期模型。鉴于人ipRGC中的色素黑视素似乎也是一种色素，最近发表和提出的研究提高了酶促视觉循环也与人黑视素结合使用的可能性。 公共卫生相关性：许多影响视觉周期的疾病会导致视网膜变性。该项目的目标是利用果蝇的分子遗传学方法，以确定视觉周期缺陷导致视网膜变性的潜在基础。

DESCRIPTION (provided by applicant): Light detection is initiated by photoactivation of a G protein-coupled receptor, referred to as rhodopsin. This photopigment consists of a protein component known as the opsin, and a vitamin A derivative called the chromophore. The chromophore is the light-sensitive portion of the photopigment, which undergoes a cis-trans isomerization in response to light. In mammalian rods and cones the chromophore must be regenerated through an enzymatic pathway, referred to as the visual cycle. Defects in this cycle lead to a variety of degenerative diseases affecting the eye. In Drosophila and in human intrinsically photosensitive retinal ganglion cells (ipRGCs), the chromophore is thought to remain associated with the opsin following light stimulation, and the chromophore appears to be regenerated simply by exposure to a second photon of light. Thus, it was thought that these bistable photopigments do not rely on a visual cycle. Surprisingly, it was recently discovered that a similar visual cycle exists in flies. This opens the possibility of using flies as a model organism in which to study the visual cycle and the retinal degeneration that results from its disruption. One goal of this project is to further our understanding of the basis for the retinal degeneration that results from perturbation of the Drosophila visual cycle. This will be achieved by examining the effects of mutations disrupting genes that function in the visual cycle, using a combination of biochemical, cell biological and genetic approaches. A second goal of this project is to use genetic and biochemical approaches to test the newly formulated model for the Drosophila visual cycle. Given that the photopigment in human ipRGCs, melanopsin, also appears to be a bistable photopigment, the recently published and proposed studies raise the possilbility that an enzymatic visual cycle is also used in conjunction with human melanopsin. PUBLIC HEALTH RELEVANCE: Many diseases affecting the visual cycle lead to retinal degeneration. The goal of this project is to exploit molecular genetic approaches in the fruit fly o identify the underlying basis of retinal degeneration that result from defects in the visual cycle.