CNTF激活Müller细胞CNTFRα-Gαi3-Gab1信号复合物抗视网膜光损伤的实验机制研究

Müller cells play pivotal roles in repairing retinal light damages. Ciliary neurotrophic factor (CNTF) is often upregulated after retinal damages, which initially activates Müller cells via binding to its receptor CNTFRα to protect retina. The potential roles of CNTF in the light-damaged retina, especially its ability to affect Müller cell behaviors, are not fully studied. Our preliminary studies have indentified two potential novel adaptor proteins for CNTFRα signaling: including inhibitory heterotrimeric G proteins α subunit 3 (Gαi3) and Grb2 associated bind 1 (Gab1). We found that CNTF induced CNTFRα-Gαi3-Gab1 association, which was required for downstream signaling transduction. shRNA silencing of Gαi3 or Gab1 inhibited CNTF-induced activation of multiple signaling pathways (Akt-mTOR, Nrf2-HO-1 and ERK-MAPK cascades), as well as Müller cell activation, survival, proliferation and anti-oxidant ability. In the current proposal, by using in vivo and in vitro models, we aim to further understand the role of Müller cells in the repair of light-damaged retina. We will also study the protective effect of CNTF against light-induced retinal damage, along with the underlying signaling mechanisms. Research efforts will be on how CNTFRα-Gαi3-Gab1 signaling complex mediates CNTF-induced PI3K-Akt-mTOR, Nrf2-HO-1 and ERK-MAPK cascades activation, and how activation of these pathways affects Müller cell functions in retina. The results of this project will provide theoretical support for using CNTF for the treatment of retinal light damage-associated diseases.

Müller细胞与视网膜损伤及修护关系密切。视网膜损伤后睫状神经营养因子（CNTF）上调，后者最初激活Müller细胞上的受体CNTFRα保护视网膜，但作用机制有待阐明。我们预实验结果证实了CNTFRα通路中2个新接头蛋白：G蛋白抑制性α亚单位3（Gαi3）和Grb2结合蛋白1（Gab1）。CNTF诱导CNTFRα-Gαi3-Gab1耦联，而shRNA敲减Gαi3或Gab1抑制CNTF诱导的PI3K-Akt-mTOR、Nrf2和ERK等通路的传导，并影响Müller细胞活化、存活、增殖及应答氧化应激能力。本研究拟应用体内外光损伤模型，从整体、细胞和分子水平观察CNTF抗光损伤的视网膜保护作用，阐明其作用机制，拟证实CNTFRα-Gαi3-Gab1信号复合物介导多条信号通路的活化是CNTF激活Müller细胞及后者抗视网膜光损伤的核心机制。旨在为运用CNTF治疗视网膜光损伤疾病提供理论支持。

视网膜损伤后睫状神经营养因子（CNTF）上调，后者最初激活Müller细胞上的受体CNTFRα保护视网膜，但作用机制有待阐明。本项目证实了CNTFRα通路中2个新接头蛋白：G蛋白抑制性α亚单位3（Gαi3）和Grb2结合蛋白1（Gab1）。CNTF诱导CNTFRα-Gαi3-Gab1耦联，而shRNA敲减Gαi3或Gab1抑制CNTF诱导的PI3K-Akt-mTOR、Nrf2和ERK等通路的传导，并影响Müller细胞活化、存活、增殖及应答氧化应激能力。本研究应用体内外光损伤模型，从整体、细胞和分子水平观察CNTF抗光损伤的视网膜保护作用，阐明其作用机制，证实CNTFRα-Gαi3-Gab1信号复合物介导多条信号通路的活化是CNTF激活Müller细胞及后者抗视网膜光损伤的核心机制。

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