Recovery of Phototransduction

光转导的恢复

基本信息

批准号：
7878632
负责人：
Ching-Kang Jason Chen
金额：
$ 37万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7878632
关键词：
Affect Binding Biochemical Breeding Cells Complex Defect Dendrites Development Electroretinography Funding G protein coupled receptor kinase GRK1 gene GRK7 gene GTP-Binding Protein Regulators Genetic Heterotrimeric GTP-Binding Proteins Human Inherited Knock-in Mouse Knock-out Knockout Mice Knowledge Light Measurement Mediating Molecular Mus Pathway interactions Phosphorylation Phosphotransferases Phototransduction Pigments Process Proteins RGS Proteins Recovery Retina Retinal Retinal Cone Retinal Diseases Rhodopsin Role Signal Transduction Testing Time Transducin Transgenic Mice Transmission Electron Microscopy Vertebrate Photoreceptors Visual Visual Signal Transduction Pathway Western Blotting cell type gain of function genetic manipulation immunocytochemistry in vivo loss of function outer plexiform layer overexpression programs promoter protein complex research study response retinal neuron retinal rods rho

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to apply the knowledge of phototransduction to understand general signaling mechanisms of heterotrimeric G-proteins. During the previous funding period we successfully identified transducin deactivation as the normal rate-limiting step of rod's recovery. We will test the generality of this finding in two other retinal G-proptein mediated pathways, namely, cone phototransduction and the mGluR6 pathway of the ON-type bipolar cells. The significance of understanding how visual signal is processed in these three cell types lies in the fact that they are adversely affected in many inherited retinal diseases. We will use gain-of-function and loss-of-function genetic manipulations in mice followed by biochemical, histological, and electrophysiological characterizations to test the following hypotheses: 1) rhodopsin deactivation is the second slowest step in rods' recovery; 2) the deactivation of cone transducin, rather than cone pigments, rate-limits normal cone recovery and 3) Gbeta5/RGS7 and Gbeta5/RGS11 protein complex are functionally redundant at the tips of the ON-type bipolar cell dendrites as the GAP for Galphao in the mGluR6 pathway. The three aims are in accordance with one of the program objectives set forth by NEI Retina Diseases Panel and have the potential to shed light into rod/cone differences and the roles of R7 RGS proteins and heterotrimeric G-proteins in the retina. This proposal examines the molecular and cellular mechanisms of visual signal transduction in retinas of genetically modified mice. The three cell types to be studied: rods, cones, and bipolar cells, are frequently affected in a variety of inherited retinal diseases.

描述（由申请人提供）：我们的长期目标是应用光转导的知识来了解异三聚体G蛋白的一般信号传导机制。在上一个融资期间，我们成功地将换蛋白停用是杆恢复的正常速率限制步骤。我们将在其他两个视网膜G-丙链蛋白介导的途径中测试这一发现的普遍性，即锥光转导和型双极细胞的MGLUR6途径。理解在这三种细胞类型中如何处理视觉信号的意义在于，它们在许多遗传性视网膜疾病中受到不利影响。我们将在小鼠中使用功能障碍和功能丧失的遗传操作，然后使用生化，组织学和电生理特征来检验以下假设：1）Rhopopsin失活是杆恢复中第二慢的一步； 2）锥体转丁蛋白的停用，而不是锥体色素，速率限制正常锥体恢复和3）GBETA5/RGS7和GBETA5/RGS11蛋白质复合物在功能上是功能多余的，这是型双极细胞树突的尖端，因为在MGLUR6 PATH中的gap palphao中的间隙。这三个目标与Nei视网膜疾病面板提出的一个程序目标之一一致，并且有可能将光线散发到杆/锥体差异以及R7 RGS蛋白和视网膜中异杀剂G蛋白的作用。该建议研究了转基因小鼠视网膜中视觉信号转导的分子和细胞机制。要研究的三种细胞类型：杆，锥和双极细胞经常在多种遗传性视网膜疾病中受到影响。