Mechanisms of NMDAR contribution to traumatic injury in retinal ganglion cells

NMDAR对视网膜神经节细胞创伤性损伤的作用机制

基本信息

批准号：
10570666
负责人：
Alon Poleg-Polsky
金额：
$ 19.44万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10570666
关键词：
Address Affect Age American Animal Model Area Automobile Driving Axon Biophysics Blindness Brain Diseases Brain region Calcium Cell Death Cell Survival Cell physiology Cells Cessation of life Development Disease Disease Management Disease Progression Early Diagnosis Early treatment Electrophysiology (science)Equilibrium Exposure to Eye Eye diseases Feedback Functional disorder Glaucoma Glutamates Goals Healthcare Human Image Impairment In Vitro Individual Injury Intervention Intrinsic factor Knowledge Learning Light Link Mediator Metabolic Metabolic stress Mission Modality Modeling Monitor Morphology Mus N-Methyl-D-Aspartate Receptors Nerve Crush Nerve Degeneration Neuronal Injury Neurons Neurotransmitters Optic Nerve Output Pathologic Pathology Pathway interactions Physiologic Intraocular Pressure Physiological Population Predisposition Preparation Prognosis Property Research Retina Retinal Degeneration Retinal Ganglion Cells Role Structure Surface Survival Rate Synapses Testing Therapeutic Intervention Trauma Traumatic Brain Injury Traumatic injury Vision Visual Work advanced disease axon injury axonopathy blind cell injury cell type demographics design excitotoxicity experimental study improved innovation insight interest mouse model nerve damage nervous system disorder neural circuit neuropathology neuroprotection novel optic nerve disorder optimal treatments preservation pressure repaired response retinal axon retinal damage retinal ganglion cell degeneration retinal neuron simulation tool visual information visual processing

项目摘要

Project Summary Glaucoma is the most prevalent cause of irreversible blindness worldwide. It is estimated that it affects over 3 million Americans and more than 100,000 are blind from this incurable disease. Often, the primary insult in glaucoma is elevated eye pressure, which leads to optic neuropathy and damage to the axons of retinal ganglion cells (RGCs). RGCs are the output neurons of the retina that carry all visual information to other brain regions; their death results in loss of visual function. Current treatment options are focused on addressing elevated intraocular pressure. While this and similar interventions can delay the progression of glaucoma, even with optimal treatment, some visual deficits occur, and vision loss is irreversible. Therefore, there is a critical need for early detection and treatment aimed at neuroprotection. Animal models have proven to be instrumental in understanding the neuropathology of RGC death. Among them, a mouse model of optic nerve crush (ONC) is of particular note because it leads to precisely timed degeneration of RGCs. Mice, like humans, have multiple RGC subtypes that differ in morphology, are embedded in separate neural circuits, and provide distinct visual functions. For reasons that have not yet been identified, many injury types disproportionately affect some RGC subtypes. Understanding the factors that promote cell survival is essential to design strategies to improve disease management. The goal of this proposal is to analyze the role of glutamatergic NMDA receptors to pathological changes in individual RGCs belonging to different subtypes. NMDA receptors are known mediators of calcium overload, excitotoxicity, and their abnormal activation can lead to cell death via multiple pathways. We will take an innovative approach that combines biophysically realistic modeling, electrophysiology, as well as glutamate and calcium imaging to provide a detailed description of the changes in the structure and function of RGCs subjected to traumatic damage. We will focus on the physiological status and responsiveness to stimulation in the injured neuron. This will enable us to elucidate the differences in the metabolic state of the cells and the contribution of parameters associated with the neuronal activity to visual deficits and prognosis. The proposed research will substantially advance our understanding of the mechanisms involved in neuronal responses to damage. The lessons learned in RGC populations will be combined and integrated to develop a comprehensive theoretical description of the impact of neuronal activity on survival after an insult and readily generalized to provide further understanding of other neuropathological conditions. Finally, our research will identify novel targets for potential neuroprotective interventions to preserve visual function.

项目概要青光眼是全世界不可逆转失明的最常见原因。估计影响超过3个数百万美国人和超过 10 万人因这种不治之症而失明。通常，主要的侮辱是青光眼是眼压升高，导致视神经病变和视网膜轴突损伤神经节细胞（RGC）。 RGC 是视网膜的输出神经元，将所有视觉信息传递到其他大脑地区；他们的死亡导致视觉功能丧失。目前的治疗方案主要集中于解决眼压升高。虽然这种干预措施和类似的干预措施可以延缓青光眼的进展，但经过最佳治疗后，会出现一些视力缺陷，并且视力丧失是不可逆转的。因此，有一个关键的需要早期发现和治疗以保护神经。动物模型已被证明有助于了解 RGC 死亡的神经病理学。之中其中，视神经挤压 (ONC) 的小鼠模型特别值得注意，因为它会导致精确定时的 RGC 退化。与人类一样，小鼠也有多种形态不同的 RGC 亚型，嵌入单独的神经回路中，并提供不同的视觉功能。由于尚未解决的原因已发现，许多损伤类型不成比例地影响某些 RGC 亚型。了解影响因素促进细胞存活对于设计改善疾病管理的策略至关重要。本提案的目的是分析谷氨酸能 NMDA 受体对病理变化的作用属于不同亚型的各个 RGC。 NMDA 受体是已知的钙超载介质，兴奋性毒性及其异常激活可通过多种途径导致细胞死亡。我们将采取结合生物物理真实建模、电生理学以及谷氨酸的创新方法和钙成像，详细描述 RGC 结构和功能的变化遭受外伤。我们将重点关注生理状态和对刺激的反应受伤的神经元。这将使我们能够阐明细胞代谢状态和与神经元活动相关的参数对视觉缺陷和预后的贡献。拟议的研究将大大增进我们对神经元参与机制的理解对损害的反应。 RGC 人群中吸取的经验教训将被结合和整合，以制定一个神经元活动对损伤后生存影响的全面理论描述，并且很容易推广以提供对其他神经病理学状况的进一步了解。最后，我们的研究将确定潜在神经保护干预措施的新目标，以保护视觉功能。