Retinal Ganglion Cell Plasticity in Glaucoma

青光眼视网膜神经节细胞可塑性

基本信息

批准号：
8893991
负责人：
VITTORIO PORCIATTI
金额：
$ 33.6万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893991
关键词：
Axon Biological Markers Biomechanics Blindness Cell Death Cell physiology Cessation of life Chronic Congenic Mice Contralateral Dependence Disease Electroretinography Environment Etiology Evoked Potentials Eye Failure Functional disorder Glaucoma Goals Homeostasis Human Immunohistochemistry Individual Influentials Lesion Light Measurement Measures Metabolic Metabolic stress Methods Modeling Molecular Monitor Motion Multiple Sclerosis Mus Neurodegenerative Disorders Onset of illness Open-Angle Glaucoma Optic Neuritis Optical Coherence Tomography Outcome Pathway interactions Pattern Plastics Posture Predisposition Prevention Process Research Retina Retinal Retinal Ganglion Cells Signal Transduction Staging Stress Testing Therapeutic Therapeutic Intervention Thick Time Transgenic Mice Transgenic Organisms Visual evoked cortical potential base clinical practice critical period improved innovation mouse model neurotrophic factor optic nerve disorder prevent response retinal nerve fiber layer stressor superior colliculus Corpora quadrigemina time use treatment effect

项目摘要

DESCRIPTION (provided by applicant): Retinal ganglion cell (RGC) death is the primary cause of irreversible blindness in Open Angle Glaucoma (OAG) and most optic neuropathies. The goal of this project is to prevent blindness in these diseases by obtaining the information needed to understand the etiology of RGC vulnerability, and use this understanding to develop approaches that prevent cell death. Our objective is determining RGC susceptibility to stressors such as IOP elevation, metabolic load, and neurotrophic factor (NT) deficiency in mouse models of glaucoma and optic neuropathy during the stage of progressive RGC dysfunction preceding death (critical period). Our central hypothesis is that RGC death is the result of failure of autoregulatory/adaptive processes that can no longer sustain normal RGC homeostasis, resulting in loss of RGC electrical responsiveness. During the critical period, RGC responsiveness is modifiable (plastic) upon stressors such as IOP, metabolic demand and NT support, thus providing a rationale and a target for therapeutic intervention. Using innovative methods, we will acutely modulate the levels of these stressors and simultaneously assess modifiability of RGC electrical responsiveness over time using pattern electroretinogram (PERG) and visual evoked potential (VEP). We will also use state-of-the-art optical coherence tomography (OCT) to serially monitor thickness of inner retinal layers, as well as retinal immunohistochemistry at endpoint. We will attain our goal and objective by accomplishing the following aims: 1) Test the hypothesis that RGC plasticity occurs in a specific time window in mouse models of glaucoma and optic neuropathy. Models will be the Myoc transgenic mouse of glaucoma, the ND4 transgenic mouse of multiple sclerosis, and the MOG-specific TCR transgenic mouse of optic neuritis. Controls will be corresponding non-pathological congenic mice. We will non-invasively alter either IOP with changes of body posture, or the metabolic demand with flickering light, and will measure corresponding changes of the PERG/VEP signal that precede loss of OCT signal; 2) Test the hypothesis that RGC plasticity is inducible in mouse models of chronic NT deficiency. We will perform unilateral lesions of the superior colliculus (SC) in C57BL/6J and DBA/2J mice and will quantify changes of the PERG and OCT signal in each eye. We will also induce IOP and metabolic stress in SC-lesioned mice to quantify acquired susceptibility of the PERG signal. Successful completion of our research will establish a new conceptual model of RGC susceptibility, and will improve our technical capability of detecting diseases' onset, monitoring their progression and the effect of treatment, eventually changing clinical practice. This will represent a significant advancement in the field and will be influential on future research on glaucoma and other neurodegenerative diseases involving RGC.

描述（由申请人提供）：视网膜神经节细胞（RGC）死亡是开放角度青光眼（OAG）和大多数光学神经病的不可逆失明的主要原因。该项目的目的是通过获得了解RGC脆弱性的病因所需的信息来防止这些疾病的失明，并利用这种理解来开发防止细胞死亡的方法。我们的目标是确定RGC对压力源的敏感性，例如IOP升高，代谢负荷和神经营养因子（NT）缺乏症在渐进性RGC功能障碍阶段（关键时期）阶段（关键时期）。我们的中心假设是RGC死亡是无法再维持正常RGC稳态的自动调节/适应过程失败的结果，导致RGC电反应能力丧失。在关键时期，RGC响应能力是可修改的（塑性），例如IOP，代谢需求和NT支持，从而提供了理由和治疗干预的靶标。使用创新方法，我们将使用模式电图（PERG）和视觉诱发电位（VEP）敏锐地调节这些应力源的水平，并同时评估RGC电响应能力的可修改性。我们还将使用最先进的光学相干断层扫描（OCT）来监测视网膜内部层的厚度，以及端点的视网膜免疫组织化学。我们将通过实现以下目标来实现我们的目标和目标：1）测试RGC可塑性在青光眼和视神经病变小鼠模型中发生的假设。模型将是青光眼的MYOC转基因小鼠，多发性硬化症的ND4转基因小鼠和MOG特异性的视神经炎的TCR转基因小鼠。对照将是相应的非病理先天小鼠。我们将随着身体姿势变化的变化或闪烁的光的代谢需求而非侵入性改变IOP，并将测量PERG/VEP信号的相应变化，而PERG/VEP信号是OCT信号丢失之前的； 2）检验以下假设：RGC可塑性在慢性NT缺乏的小鼠模型中诱导。我们将在C57BL/6J和DBA/2J小鼠中执行上凸孔（SC）的单侧病变，并将量化每只眼睛中PERG和OCT信号的变化。我们还将在SC剂量小鼠中诱导IOP和代谢应激，以量化PERG信号的获得性敏感性。成功完成我们的研究将建立一个新的RGC易感性概念模型，并将提高我们检测疾病发作，监测其进展和治疗效果的技术能力，最终改变临床实践。这将代表该领域的重大进步，并将对涉及RGC的青光眼和其他神经退行性疾病的未来研究产生影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice.

通过靶向序列修饰的腺相关病毒将突变型 NADH 脱氢酶亚基 4 基因递送至线粒体，可诱导小鼠视力丧失和视神经萎缩。

DOI：
发表时间：
2012
期刊：
Molecular vision
影响因子：
2.2
作者：
Yu,Hong;Ozdemir,SacideS;Koilkonda,RajeshwariD;Chou,Tsung-Han;Porciatti,Vittorio;Chiodo,Vince;Boye,SanfordL;Hauswirth,WilliamW;Lewin,AlfredS;Guy,John
通讯作者：
Guy,John

Head-up tilt lowers IOP and improves RGC dysfunction in glaucomatous DBA/2J mice.

平视倾斜可降低青光眼 DBA/2J 小鼠的 IOP 并改善 RGC 功能障碍。