ROD AND CONE SIGNALING PATHWAYS IN MAMMALIAN RETINA

哺乳动物视网膜中的视杆细胞和视锥细胞信号通路

• 批准号: 8573191
• 负责人: Samuel M Wu
• 金额: $ 39.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573191
• 关键词: Accounting; Alpha Cell; Amacrine Cells; Basic Science; Cations; Cell physiology; Cells; Characteristics; Chloride Ion; Chlorides; Disease; Disease model; Dyes; Electrodes; Eye; Eye diseases; Feedback; Functional disorder; Funding; GABA Receptor; Genes; Glaucoma; Glycine Receptors; Goals; Grant; Health; Image; Individual; Investigation; Knock-out; Knowledge; Label; Leber' s disease; Light; Light Cell; Mediating; Minor; Mus; Mutant Strains Mice; Neurons; Night Blindness; Pathway interactions; Pattern; Pharmacotherapy; Physiological; Process; Prosthesis; Relative (related person); Research; Research Priority; Research Project Grants; Retina; Retinal; Retinal Cone; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Scheme; Signal Pathway; Signal Transduction; Staining method; Stains; Synapses; Synaptic Transmission; Techniques; Transgenic Mice; Transgenic Organisms; Translational Research; Vertebrate Photoreceptors; Voltage-Clamp Technics; cell type; computerized data processing; design; ganglion cell; knowledge base; mouse model; neural circuit; neurobiotin; postsynaptic; presynaptic; response; retinal neuron; retinal rods; transmission process; visual information; visual process; visual processing

DESCRIPTION (provided by applicant): In this competing renewal application, we propose to continue and extend our investigations on rod and cone signaling pathways at the bipolar cell (BC), amacrine cell (AC) and ganglion cell (GC) levels in the dark-adapted mouse retina. We will focus our efforts to study the BC and AC synaptic circuitries mediating rod, M-cone and M/S-cone signal transmission to three types of alpha ganglion cells (alphaGCs), and to determine how glycinergic and GABAergic ACs regulate light-evoked signals in alphaGCs via the AC cone BC GC feedback pathways and the AC GC feedforward synapses. There are three specific aims: (1) to correlate physiological BC types with anatomical BC types in the three alphaGC circuitries and to identify possible synaptic contacts between rods/cones and BCs and between BCs and alphaGCs; (2) to determine the relative strengths of rod- and cone-mediated inputs to BCs and alphaGCs and mechanisms of signal integration in the 3 alphaGC circuitries by analyzing BCs' and alphaGCs' light-evoked cation currents ( IC) in wildtype, Tralpha-/- and Gnat2cplf3 mice; and (3) to determine relative glycinergic and GABAergic AC contributions to alphaGCs' light-evoked inhibitory and BC synaptic inputs and possible synaptic connectivity between individual GABAergic ACs and alphaGCs by double label and dual voltage clamp techniques. The goal of our research is to understand how mammalian retinal networks process visual images, a basic research priority of the NEI, and to provide crucial information on how individual retinal neurons and synapses dysfunction in disease states, such as congenital stationary night blindness and glaucoma, a translational research priority of the NEI. Moreover, knowledge of specific mammalian retinal circuitries in healthy and diseased eyes will be useful for developing new gene/drug therapies for retinal disorders, such as retinitis pigmentosa and glaucoma, as well as for designing effective retinal prosthetic devices.

描述（由申请人提供）：在这项竞争性更新申请中，我们建议继续并扩展我们对暗适应小鼠视网膜中双极细胞（BC）、无长突细胞（AC）和神经节细胞（GC）水平的视杆细胞和视锥细胞信号通路的研究。我们将致力于研究BC和AC突触回路介导的杆，M-cone和M/S-cone信号传输到三种类型的α神经节细胞（alphaGCs），并确定甘氨酸和GABA能AC如何通过AC cone BC GC反馈通路和AC GC前馈突触调节alphaGCs的光诱发信号。有三个具体目标：（1）将三个α GC回路中的生理BC类型与解剖BC类型相关联，并鉴定杆/锥和BC之间以及BC和α GC之间可能的突触接触;（2）通过分析BCs和alphaGCs的光诱发阳离子电流（IC），确定视杆细胞和视锥细胞介导的BCs和alphaGCs信号输入的相对强度，以及在3个alphaGCs回路中的信号整合机制在野生型、Tralpha-/-和Gnat 2cplf 3小鼠中;和（3）通过双标记和双电压钳技术确定甘氨酸能和GABA能AC对alphaGC的光诱发的抑制性和BC突触输入的相对贡献以及个体GABA能AC和alphaGC之间可能的突触连接。我们研究的目标是了解哺乳动物视网膜网络如何处理视觉图像，这是NEI的基础研究优先事项，并提供关于个体视网膜神经元和突触在疾病状态下功能障碍的关键信息，例如先天性静止性夜盲症和青光眼，这是NEI的转化研究优先事项。此外，健康和患病眼睛中特定哺乳动物视网膜回路的知识将有助于开发用于视网膜疾病（例如视网膜色素变性和青光眼）的新基因/药物疗法，以及用于设计有效的视网膜假体装置。