Retinal Ganglion Cell Plasticity in Glaucoma

青光眼视网膜神经节细胞可塑性

• 批准号: 8294210
• 负责人: VITTORIO PORCIATTI
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294210
• 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

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. PUBLIC HEALTH RELEVANCE: Glaucoma and optic neuropathies are leading causes of irreversible blindness, whose common cause is retinal ganglion cell (RGC) death. In this project we investigate the hypothesis that RGC dysfunction and demise is initiated by failure of autoregulatory processes that can no longer sustain normal homeostasis, resulting in progressive loss of pattern electroretinogram and susceptibility to stressors such as IOP elevation, increased metabolic demand, and neurotrophic factors deficiency. Understanding the etiology of RGC vulnerability is a necessary step to develop therapeutic approaches that reduce or eliminate its effects on cell death.

描述（由申请人提供）：视网膜神经节细胞（RGC）死亡是开角型青光眼（OAG）和大多数视神经病变不可逆失明的主要原因。该项目的目标是通过获取了解RGC易感性的病因所需的信息来预防这些疾病的失明，并利用这种了解来开发预防细胞死亡的方法。我们的目的是确定在死亡前（关键时期）进行性RGC功能障碍阶段的青光眼和视神经病变小鼠模型中RGC对压力源的易感性，如IOP升高、代谢负荷和神经营养因子（NT）缺乏。我们的中心假设是，研资局死亡是由于自我调节/适应过程失败，无法维持正常的研资局稳态，导致研资局电反应丧失。在关键时期，RGC的反应是可改变的（可塑性的），如IOP、代谢需求和NT支持等应激源，从而为治疗干预提供了理论基础和目标。使用创新的方法，我们将急性调节这些应激源的水平，同时使用模式视网膜电图（PERG）和视觉诱发电位（VEP）评估RGC电反应随时间的可变性。我们还将使用最先进的光学相干断层扫描（OCT）来连续监测视网膜内层的厚度，以及终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：1)在青光眼和视神经病变小鼠模型中验证RGC可塑性在特定时间窗内发生的假设。模型为青光眼Myoc转基因小鼠，多发性硬化症ND4转基因小鼠，视神经炎mog特异性TCR转基因小鼠。对照为相应的非病理性基因小鼠。我们将通过身体姿势的变化无创地改变眼压，或通过闪烁的光改变代谢需求，并测量OCT信号丢失之前PERG/VEP信号的相应变化；2)验证RGC可塑性在慢性NT缺乏小鼠模型中可诱导的假设。我们将对C57BL/6J和DBA/2J小鼠进行单侧上丘（SC）病变，并量化每只眼睛PERG和OCT信号的变化。我们还将在sc损伤小鼠中诱导IOP和代谢应激，以量化PERG信号的获得性敏感性。我们的研究的成功完成将建立一个新的RGC易感性概念模型，并将提高我们检测疾病发病、监测疾病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展，并将对未来涉及RGC的青光眼和其他神经退行性疾病的研究产生影响。