The roles of Gbeta5 and R7 RGS protein in vision

Gbeta5和R7 RGS蛋白在视觉中的作用

• 批准号: 8825044
• 负责人: Ching-Kang Jason Chen
• 金额: $ 6.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825044
• 关键词: roles; Gbeta5; R7; RGS; protein

DESCRIPTION (provided by applicant): The role of heterotrimeric G-proteins in human biology is best represented by rhodopsin/transducin signaling in rod phototransduction. Ironically, how other G-proteins subserve mammalian vision outside photoreceptors is poorly understood. This application will start to fill this knowledge gap by elucidating the roles of the fifth Gb subunit (Gb5) and its obligate partners R7 RGS proteins (RGS6, RGS7, RGS9, RGS11) in mouse retina. We have found a multitude of visual defects in Gb5-/- mice which include: 1) delayed phototransduction recovery; 2) abnormal retinal waves and incomplete refinement of retinogeniculate projections during postnatal development; 3) lack of ERG b-wave; 4) reduced starburst amacrine cell (SAC) dendritic field; and 5) disrupted triadic ribbon synapses in retinal outer plexiform layer. We hypothesize that Gb5 works exclusively with R7 RGS proteins in vivo by stabilizing them and that in its absence the signaling state of Gao is abnormally prolonged to cause these visual defects. A multidisciplinary approach with four independent aims will critically examine the pathologic mechanisms of aforementioned Gb5-/- mouse visual defects. Aim-1 will test the exclusivity of the interaction between Gb5 and R7 RGS proteins by examining the level of Gb5 in various tissues of mutant mice with permutated and total loss of the four R7 RGS genes. Aim- 2 will test whether RGS7 and RGS11 expression is required in a cell autonomous manner for normal development and function of depolarizing bipolar cell (DBC). Aim-3 will examine whether normal SAC structure and function requires RGS6 and RGS7 during retinal development. Aim-4 will test whether prolonged Gao signaling retards dendritic development in various retinal cells including DBCs, SACs, and certain retinal ganglion cells (RGCs) and whether it underlies the dendritic defects observed in these retinal neurons in the absence of Gb5. By completing these aims we expect to significantly advance the heterotrimeric G-protein and the vision fields by firmly establishing the roles of Gb5, R7 RGS, and Gao in the visual system.

描述（由申请人提供）：异三聚体G蛋白在人类生物学中的作用最好以ROD Phototransduction在Rod Phototransduction中的视紫红质/跨丁蛋白信号来表示。具有讽刺意味的是，其他G蛋白如何在光感受之外予以肯定的哺乳动物视力知之甚少。该应用程序将通过阐明第五GB亚基（GB5）的角色及其强制伙伴R7 RGS蛋白（RGS6，RGS7，RGS7，RGS9，RGS11）在小鼠视网膜中的角色来开始填补这一知识差距。我们在GB5 - / - 小鼠中发现了许多视觉缺陷，其中包括：1）延迟的光转导回收； 2）在产后发育过程中视网膜生成投影的视网膜波异常和不完整的细化； 3）缺乏ERG B波； 4）减少了starburst amacrine细胞（SAC）树突状场； 5）视网膜外丛状层中破坏了三合会色带突触。我们假设GB5通过稳定在体内与R7 RGS蛋白专门工作，并且在缺乏GAO的信号状态异常延长以引起这些视觉缺陷。具有四个独立目标的多学科方法将严格检查上述GB5 - / - 小鼠视觉缺陷的病理机制。 AIM-1将通过检查突变小鼠的各种组织中的GB5水平，并以四个R7 RGS基因的总损失来测试GB5和R7 RGS蛋白之间相互作用的排他性。 AIM-2将以细胞自主的方式测试RGS7和RGS11表达是否需要用于去极化双极细胞（DBC）的正常发育和功能。 AIM-3将检查正常的SAC结构和功能是否需要视网膜发育过程中RGS6和RGS7。 AIM-4将测试长时间的GAO信号传导是否延迟了各种视网膜细胞中的树突发育，包括DBC，SACS和某些视网膜神经节细胞（RGC）以及它是否在缺乏GB5的视网膜神经元中观察到的树突状缺陷是基的。通过完成这些目标，我们希望通过牢固确定GB5，R7 RGS和GAO在视觉系统中的角色来显着提高异构三聚体G蛋白和视觉领域。