Isolation of congenital stationary night blindness genes

先天性静止性夜盲症基因的分离

• 批准号: 7681025
• 负责人: RONALD G GREGG
• 金额: $ 39.23万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681025
• 关键词: Binding; Biochemical; Blindness; Brain; Calcium Channel; Candidate Disease Gene; Cations; Cells; Complex; Defect; Dendrites; Disease; Electroretinography; Elements; Extracellular Matrix Proteins; Family; Family member; Feedback; Funding; Genes; Glutamate Receptor; Glutamates; Goals; Grant; Human; Hybrids; Immunoprecipitation; Individual; Knockout Mice; Lateral; Lead; Leucine-Rich Repeat; Ligands; Light; Link; Mass Spectrum Analysis; Mediating; Metabotropic Glutamate Receptors; Molecular; Mus; Mutant Strains Mice; Mutation; Nature; Neurons; Neurotransmitters; Night Blindness; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Photoreceptors; Property; Proteins; Proteoglycan; Retina; Retinal; Retinal Cone; Role; Signal Transduction; Site; Structure; Structure-Activity Relationship; Synapses; Synaptic Transmission; Vision; Yeasts; blind; extracellular; ganglion cell; glycosylation; horizontal cell; in vivo; member; mouse model; mutant; neurotransmitter release; patch clamp; postsynaptic; presynaptic; protein transport; public health relevance; research study; response; retinal rods; transmission process

DESCRIPTION (provided by applicant): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter, glutamate, from cone and rod photoreceptor terminals, and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition. There are two classes of bipolar cells, hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor, mGluR6, and depolarize in response to a light flash. Defects in transmission between photoreceptors and bipolar cells result in several forms of congenital stationary night blindness (CSNB). The incomplete form, CSNB2, results from mutations in genes critical to glutamate release in photoreceptors, including the 11F subunit of voltage dependent calcium channels. The complete form emerges from mutations in signaling in DBCs, which include mutations in mGluR6 and nyctalopin (a protein of unknown function). Signaling through DBCs is mediated via a metabotropic glutamate receptor, mGluR6, which modulates the activity of a non-specific cation channel of unknown identity. The details of this mGluR6 cascade are mostly unknown. The long term goal of this project is to characterize the molecular components required for synaptic transmission between photoreceptors and DBCs. This project has four specific aims: 1) determine the structure/function relationships of nyctalopin, 2) determine the state of the non-specific cation channel in several night blind mice, 3) determine the binding partners of nyctalopin, thereby elucidating new component of the mGluR6 cascade, and 4) create knockout mouse lines of the nyctalopin interacting proteins to determine if they result in nigh blindness. At the completion of this project, we will have identified new members critical to signal transmission in DBCs. Further, we will have identified new candidate genes for congenital stationary night blindness. PUBLIC HEALTH RELEVANCE: Vision requires a light signal to be converted to an electrical signal, which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second neuron in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function.

描述（由申请人提供）：当光在感光器中转换为电信号时，视觉开始。光照的增加会减少视锥细胞和视杆细胞末端的神经递质谷氨酸的释放，而光照的减少会增加其释放。突触谷氨酸浓度的这些变化由两类双极细胞检测到，然后将信号通过视网膜回路垂直传输到神经节细胞。神经递质的变化也可以通过水平细胞检测到，水平细胞以反馈和前馈抑制的形式提供横向传输。双极细胞有两类：超极化 (HBC) 和去极化 (DBC)。 HBC 利用离子型谷氨酸受体并响应闪光而超极化。 DBC 利用代谢型谷氨酸受体 mGluR6，并响应闪光而去极化。光感受器和双极细胞之间的传输缺陷会导致多种形式的先天性静止性夜盲症 (CSNB)。不完整形式 CSNB2 是由对光感受器中谷氨酸释放至关重要的基因突变引起的，包括电压依赖性钙通道的 11F 亚基。完整的形式源于 DBC 信号传导的突变，其中包括 mGluR6 和 nyctalopin（一种功能未知的蛋白质）的突变。通过 DBC 的信号传导是通过代谢型谷氨酸受体 mGluR6 介导的，它调节未知身份的非特异性阳离子通道的活性。 mGluR6 级联的细节大多未知。该项目的长期目标是表征光感受器和 DBC 之间突触传递所需的分子成分。该项目有四个具体目标：1) 确定 nyctalopin 的结构/功能关系，2) 确定几只夜盲小鼠中非特异性阳离子通道的状态，3) 确定 nyctalopin 的结合伴侣，从而阐明 mGluR6 级联的新成分，4) 创建 nyctalopin 相互作用蛋白的敲除小鼠品系，以确定它们是否会导致夜盲症。该项目完成后，我们将确定对 DBC 信号传输至关重要的新成员。此外，我们还将鉴定出先天性静止性夜盲症的新候选基因。 公共健康相关性：视觉需要将光信号转换为电信号，然后通过神经元网络传输到大脑。正在研究的这组疾病被称为先天性静止性夜盲症。它们在光感受器和通路中的第二个神经元之间的信号传输方面存在缺陷。该提案中的研究将描述缺陷的性质并确定对功能至关重要的新蛋白质。