CaMKII-mediated Neuroprotection of Retinal Ganglion Cells

CaMKII 介导的视网膜神经节细胞的神经保护

• 批准号: 10018039
• 负责人: Bo Chen
• 金额: $ 59.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018039
• 关键词: Acute; Apoptosis; Autophagocytosis; Axon; Blindness; Brain; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Cause of Death; Cell Death; Cell physiology; Chronic; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Cytoprotection; Electrophysiology (science); Foundations; Functional disorder; Glaucoma; Goals; Human Characteristics; Mediating; Microspheres; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Crush; Neurodegenerative Disorders; Neurons; Ocular Hypertension; Optic Nerve; Optic Nerve Injuries; Output; Oxidative Stress; Pathogenesis; Pathway interactions; Physiologic Intraocular Pressure; Play; Process; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Testing; Therapeutic; Vision; Visual impairment; area striata; axon injury; axon regeneration; calmodulin-dependent protein kinase II; deprivation; design; endoplasmic reticulum stress; excitotoxicity; experimental study; functional outcomes; glial activation; human disease; mitochondrial dysfunction; nerve injury; neuron loss; neuronal cell body; neuroprotection; neurotrophic factor; optic nerve disorder; preservation; protein misfolding; restoration; retinal damage; retinal ganglion cell degeneration; retinal neuron; therapeutic evaluation; therapeutic target

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.

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特别容易受到伤害 他们因各种侮辱而不可逆转地损害。 RGC的丧失是视力障碍的主要原因， 全球盲目。为了保留RGC，已经致力于剖析广泛的研究工作 消除不同侮辱群体引起的RGC死亡的信号传导机制。理解 导致RGC死亡的各种侮辱引发的途径将有助于治疗的设计 保存RGC的策略。钙信号传导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）在协调和执行中起着核心作用 钙信号。 CAMKII在RGC死亡中的确切作用尚待确定。我们假设这一点 对RGC的多种侮辱可能会扰动Camkii及其下游信号，导致RGC死亡。我们进一步 CAMKII活动调节和CAMKII下游效应子的原因可能会提供一般性 保护RGC免受各种侮辱。我们研究的长期目标是了解 RGC死亡潜在的分子机制，并制定治疗策略以保护 通常死于患病的视网膜（例如青光眼）的RGC。我们建议研究Camkii的作用 以及由三种不同的侮辱引起的RGC死亡中CaMKII的下游信号（NMDA兴奋性， 视神经损伤和眼高血压），代表对RGC的急性和长期侮辱 以下目的：目标1）我们将调查CAMKII及其下游信号在保护RGC中的作用 NMDA兴奋性毒性的SOMA和轴突。目的2）我们将调查Camkii及其下游的作用 保护RGC SOMA和轴突免受视神经损伤的信号传导。目标3）我们将调查Camkii- 眼高血压的微叶片闭塞模型中介导的RGC保护，并检查CAMKII-是否是否 介导的RGC保护恢复了急性和慢性损伤模型中的视觉功能。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，在 RGC SOMA和轴突的变性，由代表急性和慢性的各种侮辱引起 损害赔偿，我们拟议的研究将为CAMKII提供科学基础，作为治疗目标 RGC保护和视力恢复。