Light Activation of Retinal Insulin Receptor Signaling

项目摘要/摘要 在过去的十年里，我们实验室的研究发现了一种 杆状感光器中依赖光的胰岛素受体(IR)信号通路。我们有 发现IR的激活对视杆存活具有重要的功能，因为它在 RODS导致神经保护性生存信号的丢失。这条新的路径使用 生长因子受体结合蛋白(Grb14)，IR的上游调节因子，需要 用于膜靶向的视紫红质光漂白。Grb14保护光依赖的IR 激活杆状感光细胞以对抗PTP1B的去磷酸化。光活化红外 随后与磷脂酰肌醇3-激酶(PI3K)相关，PI3K是细胞生存因子， 从而调节下游的生存途径。这些研究表明 视紫红质光激发可能触发经典信号事件以外的信号事件 转导蛋白激活。最近，有研究表明，IR信号通路是 视网膜色素变性(RP)模型中视锥感光细胞存活的重要因素 全身注射胰岛素可延缓视锥感光细胞的死亡。我们发现 胰岛素样生长因子-1受体(IGF-1R)也能激活PI3K和Akt的存活 在光胁迫下杆状体内的途径。我们的假设是IR/IGF-1R信号 路径对杆状和圆锥体的生存和维持很重要 光感受器的结构和功能。我们项目的长期目标是获得 更好地理解细胞内信号通路，为 对视杆细胞和视锥感光细胞的神经保护。具体目标是 探讨IR和IGF-1R在光感受器结构和功能调节中的作用 功能。为此，我们将确定Grb14激活IR的机制 并确定IR和IGF-1R在视杆细胞和视锥细胞中的功能作用 细胞。我们将利用遗传、分子和生化方法的组合来 解决我们的具体目标。这些研究的结果将有助于更好地理解 IR和IGF-1R信号在光感受器结构、功能和存活中的作用。

Project Summary/Abstract Studies from our laboratory over the past decade have found the existence of a novel light-dependent insulin receptor (IR) signaling pathway in rod photoreceptors. We have discovered that IR activation is functionally important for rod survival, since its deletion in rods resulted in the loss of neuroprotective survival signaling. This novel pathway uses growth factor receptor bound protein (Grb14), an upstream regulator of IR, and requires photobleaching of rhodopsin for membrane targeting. Grb14 protects light-dependent IR activation in rod photoreceptors against dephosphorylation by PTP1B. Light-activated IR is subsequently associated with phosphoinositide 3-kinase (PI3K), a cell survival factor, and thus regulates the downstream survival pathway. These studies suggest that rhodopsin photoexcitation may trigger signaling events alternative to the classical transducin activation. Recently, it was suggested that the IR signaling pathway is important for cone photoreceptor survival in retinitis pigmentosa (RP) models since systemic administration of insulin delays the death of cone photoreceptors. We found that insulin-like growth factor-1 receptor (IGF-1R) also activates PI3K and Akt survival pathway in rods under light stress. It is our hypothesis that IR/IGF-1R signaling pathways are important for survival and maintenance of rod and cone photoreceptor structure and function. The long-term goal of our project is to gain a greater understanding of the intracellular signaling pathways that provide neuroprotection to both rod and cone photoreceptor cells. The specific objective is to investigate the role of IR and IGF-1R in the regulation of photoreceptor structure and function. To this end, we will determine the mechanism by which Grb14 activates the IR and determine the functional roles of IR and IGF-1R in both rod and cone photoreceptor cells. We will utilize a combination of genetic, molecular, and biochemical approaches to address our specific aims. Results from these studies will lead to a better understanding the roles of IR and IGF-1R signaling in photoreceptor structure, function and survival.