CaMKII-mediated Neuroprotection of Retinal Ganglion Cells

项目摘要/摘要： 视网膜神经节细胞(RGC)是视网膜的输出神经元。RGC特别容易受到攻击，因为 他们受到各种各样的侮辱，受到了不可逆转的损害。视网膜节细胞的丧失是视力受损的主要原因 世界范围内的失明。为了保存视网膜神经节细胞，人们对其进行了广泛的研究 找出了RGC死亡背后的信号机制，这些机制是由不同的侮辱组造成的。理解 各种侮辱导致RGC死亡的通路将有助于治疗性设计 拯救RGC的策略。钙信号调节细胞过程和功能的许多方面。 钙/钙调蛋白依赖的蛋白激酶II(CaMKII)在协调和执行过程中起着核心作用 钙信号。CaMKII在RGC死亡中的确切作用仍有待确定。我们假设 对RGC的不同侮辱可能扰乱CaMKII及其下游信号，导致RGC死亡。我们进一步 CaMKII活性和CaMKII下游效应子的调节可能提供一般的 保护RGC免受各种侮辱。我们研究的长期目标是了解 RGC死亡的分子机制，并开发保护RGC的治疗策略 视网膜神经节细胞通常在病变的视网膜中死亡，如青光眼。我们建议研究CaMKII的作用 CaMKII在三种不同损伤诱导的RGC死亡中的下游信号转导(NMDA兴奋性毒性， 视神经损伤和高眼压)代表对视网膜节细胞的急性和慢性侮辱，通过 目的：1)研究CaMKII及其下游信号通路在保护RGC中的作用 NMDA兴奋性毒性引起的胞体和轴突。目的2)我们将研究CaMKII及其下游的作用 保护RGC胞体和轴突免受视神经损伤的信号转导。目标3)我们将调查CaMKII- 介导RGC在微球阻塞高眼压模型中的保护作用，并检测CaMKII- RGC介导性保护在急性和慢性损伤模型中均可恢复视功能。总而言之， 拟议的研究将有助于阐明CaMKII在分子和细胞水平上的作用， 急性和慢性不同侮辱引起的RGC胞体和轴突变性 我们提出的研究将为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.