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）：异源三聚体 G 蛋白在人类生物学中的作用最好由视杆光转导中的视紫红质/转导蛋白信号传导来体现。讽刺的是，人们对其他 G 蛋白如何促进哺乳动物光感受器之外的视力知之甚少。该应用将通过阐明第五个 Gb 亚基 (Gb5) 及其专性伙伴 R7 RGS 蛋白（RGS6、RGS7、RGS9、RGS11）在小鼠视网膜中的作用来开始填补这一知识空白。我们发现 Gb5-/- 小鼠存在多种视觉缺陷，其中包括：1）光转导恢复延迟； 2) 出生后发育过程中视网膜电波异常和视黄质突起的细化不完全； 3) ERG b波缺失； 4) 星爆无长突细胞（SAC）树突状区域减少； 5) 视网膜外丛状层中的三元带状突触被破坏。我们假设 Gb5 在体内专门与 R7 RGS 蛋白一起发挥作用，稳定它们，并且在其不存在的情况下，Gao 的信号传导状态异常延长，从而导致这些视觉缺陷。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 将通过检查四个 R7 RGS 基因排列和完全丢失的突变小鼠各种组织中 Gb5 的水平来测试 Gb5 和 R7 RGS 蛋白之间相互作用的排他性。 Aim-2 将测试去极化双极细胞 (DBC) 的正常发育和功能是否需要以细胞自主方式表达 RGS7 和 RGS11。 Aim-3将检查视网膜发育过程中正常的SAC结构和功能是否需要RGS6和RGS7。 Aim-4将测试延长的Gao信号传导是否会阻碍各种视网膜细胞（包括DBC、SAC和某些视网膜神经节细胞（RGC））的树突发育，以及它是否是在没​​有Gb5的情况下在这些视网膜神经元中观察到的树突缺陷的基础。通过完成这些目标，我们期望通过牢固确立 Gb5、R7 RGS 和 Gang 在视觉系统中的作用，显着推进异源三聚体 G 蛋白和视野。