Neuroprotection Mechanism for Photoreceptors

项目摘要/摘要 当细胞外信号分子激活位于细胞上的特定受体时，信号转导就发生了 细胞表面或细胞内部。反过来，这种受体触发了细胞内的一系列生化反应， 创建响应。胰岛素样生长因子-1受体介导的信号网络是 对许多细胞功能的调节至关重要，包括神经保护 有丝分裂后细胞。本申请的具体目的是研究IGF-1R的作用机制。 在视杆细胞和视锥细胞感受器中介导的信号和细胞过程的调节 促进和维持光感受器的功能和生存能力。 这项建议中概述的研究战略是建立在最近发现的IGF-1R在 光感受器神经保护，以及IGF-1R在许多其他细胞组织中的基本特性。这项研究 这里提出的将定义IGF-1R如何调节光感受器功能。使用转基因小鼠 和药物，我们已经确定了细胞信号和基因表达的变化 视网膜。我们已经在视网膜中发现了几种IGF-1R信号的激活剂和负调控因子，以及 已经开发出操纵IGF-1R激活的方法，以检测对光感受器功能的影响。 我们将使用这些方法来确定IGF-1R信号如何调节光感受器神经保护和 其他细胞功能。我们将研究IGF-1的来源以激活IGF-1R及其后果 棒材缺失(目标1)。我们将测试视网膜中IGF-1R的激活和失活机制(AIM 2)。 成功完成我们的研究可能会使数百万因视杆细胞和视锥细胞丢失而失明的人受益。 我们新的和创新的方法将促进我们工作的未来翻译应用，目标是 将我们的发现应用于治疗人类视网膜退行性变。阐明这些机制是至关重要的。 促进我们对光感受器细胞基本生物学和致病生物学机制的理解 光感受器退化，常与合成代谢过程中的缺陷有关。

PROJECT SUMMARY/ABSTRACT Signal transduction occurs when an extracellular signaling molecule activates a specific receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response. The signaling network mediated by insulin-like growth factor 1 (IGF-1) receptor is fundamentally important for the regulation of a number of cellular functions, including the neuroprotection of post-mitotic cells. The specific objectives of this application are to investigate the mechanism of IGF-1R- mediated signaling in both rod and cone photoreceptors, and the regulation of the cellular processes required to promote and sustain photoreceptor functionality and viability. The research strategy outlined in this proposal is built upon the recently uncovered function of IGF-1R in photoreceptor neuroprotection, and a fundamental property of IGF-1R in many other cell tissues. The study proposed herein will define how IGF-1R regulates photoreceptor functions. Using genetically modified mice and pharmacological agents, we have identified changes in cellular signaling and gene expression in the retina. We have identified several activators and negative regulators of IGF-1R signaling in the retina, and have developed methods for manipulating IGF-1R activation to detect the impact on photoreceptor functions. We will use these methods to determine how IGF-1R signaling regulates photoreceptor neuroprotection and other cellular functions. We will study the source of IGF-1 to activate IGF-1R and the consequence of its absence in rods (Aim 1). We will test the mechanisms of IGF-1R activation and deactivation in the retina (Aim 2). Successful completion of our studies could benefit millions of people who are blind from rod and cone cell loss. Our new and innovative approaches will facilitate future translational application of our work, with the goal of applying our findings to the treatment of human retinal degenerations. Elucidating these mechanisms is critical to advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying the photoreceptor degeneration that is frequently associated with defects in anabolic processes.