Molecular Mechanisms of Retinal Degeneration and the visual cycle in Drosophila

果蝇视网膜变性和视觉周期的分子机制

• 批准号: 8314977
• 负责人: David Samuel Ronderos
• 金额: $ 3.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2013-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314977
• 关键词: Affect; All-Trans-Retinol; Animal Model; Back; Biochemical; Biological; Cell membrane; Cell surface; Cells; Cellular biology; Defect; Degenerative Disorder; Detection; Disease; Drosophila genus; Endocytosis; Endoplasmic Reticulum; Enzymes; Exposure to; Eye; G-Protein-Coupled Receptors; Generations; Genetic; Goals; Human; Lead; Light; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Mutation; Natural regeneration; Nutrient; Opsin; Pathway interactions; Photons; Photoreceptors; Pigments; Production; Proteins; Publishing; Research; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Retinal Pigments; Retinoids; Retinol dehydrogenase; Rhodopsin; Series; Testing; Toxic effect; Vertebrate Photoreceptors; Visual; Vitamin A; base; chromophore; cis trans isomerization; deprivation; endoplasmic reticulum stress; fly; gene function; melanopsin; mutant; photoactivation; research study; response; trafficking; visual cycle

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.

描述(申请人提供)：光检测是由G蛋白偶联受体的光激活启动的，称为视紫红质。这种感光色素由一种被称为视蛋白的蛋白质成分和一种被称为生色团的维生素A衍生物组成。生色团是光色素中对光敏感的部分，它对光做出顺反异构化反应。在哺乳动物的视杆细胞和视锥细胞中，发色团必须通过一种被称为视觉周期的酶途径来再生。这个周期中的缺陷会导致各种影响眼睛的退行性疾病。在果蝇和人类固有的光敏性视网膜神经节细胞(IpRGCs)中，生色团被认为与光刺激后的视蛋白有关，发色团似乎只需暴露在第二个光子下就能再生。因此，人们认为这些双稳感光颜料不依赖于视觉周期。令人惊讶的是，最近发现果蝇也存在类似的视觉周期。这为利用苍蝇作为模型生物来研究视觉周期和由视觉周期中断引起的视网膜退化提供了可能性。这个项目的一个目标是进一步了解由于果蝇视觉周期的扰动而导致的视网膜退化的基础。这将通过结合使用生化、细胞生物学和遗传学方法来检查破坏视觉周期中功能的基因的突变的影响来实现。该项目的第二个目标是使用遗传和生化方法来测试新形成的果蝇视觉周期模型。鉴于人类ipRGC中的光色素，即黑色素，似乎也是一种双稳定的光色素，最近发表和提出的研究提出了酶视觉周期也与人类黑素结合使用的可能性。 与公共卫生相关：许多影响视觉周期的疾病会导致视网膜退化。该项目的目标是开发果蝇的分子遗传学方法，以确定视觉周期缺陷导致视网膜退化的潜在基础。