Light Activation of Retinal Insulin Receptor Signaling

描述（由申请人提供）：在过去的十年中，我们实验室的研究发现，在杆状光感受器中存在一种新的光依赖性胰岛素受体（IR）信号通路。我们已经发现，IR激活对视杆细胞的存活具有重要的功能，因为它在视杆细胞中的缺失会导致神经保护性存活信号的丢失。这种新途径使用生长因子受体结合蛋白（Grb14）作为IR的上游调节因子，并需要视紫红质进行光漂白以实现膜靶向。Grb14保护杆状光感受器的光依赖性IR激活免受PTP1B的去磷酸化。光激活IR随后与磷酸肌肽3-激酶（PI3K）相关，PI3K是一种细胞存活因子，从而调节下游存活途径。这些研究表明，视紫红质光激发可能触发替代经典转导蛋白激活的信号事件。最近，有研究表明，胰岛素可延缓视网膜色素变性（RP）模型视锥细胞的死亡，因此IR信号通路对视锥细胞的存活起重要作用。我们发现胰岛素样生长因子-1受体（IGF-1R）也激活光应激下杆状细胞中PI3K和Akt的存活途径。我们的假设是，IR/IGF-1R信号通路对视杆和视锥细胞的光感受器结构和功能的生存和维持很重要。我们项目的长期目标是更深入地了解细胞内的信号通路，这些通路为视杆细胞和视锥细胞提供神经保护。具体目的是研究IR和IGF-1R在光感受器结构和功能调节中的作用。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。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。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Insulin receptors (IR) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). Disregulation of IR signaling in the CNS has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. In retinal rods, IR signaling is neuroprotective, and recently it was shown that insulin delays the death of cone photoreceptor in retinitis pigmentosa animal models. Besides IR, insulin-like growth factor-1 receptors (IGF-1R) are also expressed in both rods and cones; however, their functional role has not been elucidated. Our studies suggest that protein tyrosine phosphatase 1B (PTP1B) negatively regulated neuroprotective survival signaling of the IR. Our studies also suggest that a defect in the photobleaching of rhodopsin and mutations in rhodopsin gene enhances the activity of PTP1B and this activated activity could down regulate the IR survival signaling. Controlling the PTP1B activity and activating the IR signaling would provide sustained neuroprotection to both rods and cones. Our new and innovative approaches to target PTP1B will facilitate future translational application of our work, with the goal of applying our findings to the clinical care of human retinal degenerations. Studies proposed in this grant application would help to understand the functional roles of IR and IGF-1R in photoreceptor structure, function and survival.