CaMKII-mediated Neuroprotection of Retinal Ganglion Cells

项目概要/摘要： 视网膜神经节细胞（RGC）是视网膜的输出神经元。RGC特别脆弱， 他们被各种各样的侮辱不可逆转地损害了。RGC的丧失是视力障碍的主要原因， 全世界失明为了保存视网膜神经节细胞，大量的研究工作致力于解剖 揭示了不同损伤组引起RGC死亡的信号机制。理解 不同损伤导致RGC死亡的途径将有助于设计治疗方案， 拯救RGC的策略。钙信号调节细胞过程和功能的许多方面。 钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在协调和执行 钙信号CaMK II在RGC死亡中的确切作用仍有待确定。我们假设 对RGC的不同损伤可能干扰CaMKII及其下游信号传导，导致RGC死亡。我们进一步 CaMKII活性的调节和CaMKII的下游效应物可以提供一种普遍的 保护RGC免受广泛的损伤。我们研究的长期目标是了解 RGC死亡的分子机制，并制定治疗策略， RGC通常在患病的视网膜中死亡，例如青光眼。我们建议研究CaMKII的作用 以及CaMK Ⅱ在三种不同损伤（NMDA兴奋毒性， 视神经损伤和高眼压），代表对RGC的急性和慢性损伤，通过 目的1）研究CaMK Ⅱ及其下游信号通路在RGC保护中的作用 索马和轴突的NMDA兴奋毒性。目的2）我们将研究CaMK Ⅱ及其下游的作用， 信号转导在保护RGC索马和轴突免受视神经损伤中的作用。目标3）我们将研究CaMKII- 介导的RGC保护作用，并检查CaMK II- 介导的RGC保护在急性和慢性损伤模型中恢复视觉功能。总之， 拟议的研究将有助于阐明CaMKII在分子和细胞水平上的作用， 由代表急性和慢性的不同损伤诱导的RGC索马和轴突的变性 我们的研究将为CaMKII作为治疗靶点提供科学依据。 RGC保护和视力恢复。

Project Summary/Abstract: Retinal ganglion cells (RGCs) are the output neurons of the retina. RGCs are particularly vulnerable as they are irreversibly damaged by diverse insults. The loss of RGCs is a leading cause of vision impairment and blindness worldwide. In order to preserve RGCs, extensive research efforts have been devoted to dissecting out the signaling mechanisms underlying RGC death caused by the diverse groups of insults. Understanding the pathways triggered by diverse insults leading to RGC death will facilitate the design of therapeutic strategies to save RGCs. Calcium signaling regulates many aspects of cellular processes and functions. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in coordinating and executing calcium signals. The exact role of CaMKII in RGC death remains to be determined. We hypothesize that diverse insults to RGCs may perturb CaMKII and its downstream signaling, leading to RGC death. We further reason that modulation of CaMKII activity and the downstream effectors of CaMKII may provide a general protection for RGCs against a wide spectrum of insults. The long-term goal of our research is to understand the molecular mechanisms underlying RGC death, and to develop therapeutic strategies for the protection of RGCs that typically die in a diseased retina such as glaucoma. We propose to investigate the role of CaMKII and the downstream signaling of CaMKII in RGC death induced by three different insults (NMDA excitotoxicity, optic nerve injury, and ocular hypertension) representing acute and chronic insults to RGCs, through the following Aims: Aim 1) We will investigate the role of CaMKII and its downstream signaling in protecting RGC soma and axons from NMDA excitotoxicity. Aim 2) We will investigate the role of CaMKII and its downstream signaling in protecting RGC soma and axons from optic nerve injury. Aim 3) We will investigate CaMKII- mediated RGC protection in microbead occlusion model of ocular hypertension, and examine whether CaMKII- mediated RGC protection restores visual function in both acute and chronic damage models. In summary, the proposed research will help elucidate the role of CaMKII, at the molecular and cellular level, in the degeneration of RGC soma and axons induced by diverse insults representing both acute and chronic damages, and our proposed studies will provide scientific foundation for CaMKII as a therapeutic target for RGC protection and vision restoration.