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:
- 金额:$ 19.44万
- 依托单位:
- 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:
- 关键词:AddressAffectAgeAmericanAnimal ModelAreaAutomobile DrivingAxonBiophysicsBlindnessBrain DiseasesBrain regionCalciumCell DeathCell SurvivalCell physiologyCellsCessation of lifeDevelopmentDiseaseDisease ManagementDisease ProgressionEarly DiagnosisEarly treatmentElectrophysiology (science)EquilibriumExposure toEyeEye diseasesFeedbackFunctional disorderGlaucomaGlutamatesGoalsHealthcareHumanImageImpairmentIn VitroIndividualInjuryInterventionIntrinsic factorKnowledgeLearningLightLinkMediatorMetabolicMetabolic stressMissionModalityModelingMonitorMorphologyMusN-Methyl-D-Aspartate ReceptorsNerve CrushNerve DegenerationNeuronal InjuryNeuronsNeurotransmittersOptic NerveOutputPathologicPathologyPathway interactionsPhysiologic Intraocular PressurePhysiologicalPopulationPredispositionPreparationPrognosisPropertyResearchRetinaRetinal DegenerationRetinal Ganglion CellsRoleStructureSurfaceSurvival RateSynapsesTestingTherapeutic InterventionTraumaTraumatic Brain InjuryTraumatic injuryVisionVisualWorkadvanced diseaseaxon injuryaxonopathyblindcell injurycell typedemographicsdesignexcitotoxicityexperimental studyimprovedinnovationinsightinterestmouse modelnerve damagenervous system disorderneural circuitneuropathologyneuroprotectionnoveloptic nerve disorderoptimal treatmentspreservationpressurerepairedresponseretinal axonretinal damageretinal ganglion cell degenerationretinal neuronsimulationtoolvisual informationvisual 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.
项目摘要
青光眼是世界范围内最常见的不可逆性失明的原因。据估计,它影响超过3
100万美国人和10万多人因这种不治之症而失明。通常情况下,
青光眼是眼压升高,导致视神经病变和视网膜神经轴突损伤。
神经节细胞(RGCs)。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
区域;他们的死亡导致视觉功能的丧失。目前的治疗方案侧重于解决
眼压升高虽然这种和类似的干预措施可以延缓青光眼的进展,
在最佳治疗的情况下,会出现一些视力缺陷,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,目的是神经保护。
动物模型已被证明有助于理解RGC死亡的神经病理学。之间
其中,视神经挤压(ONC)的小鼠模型特别值得注意,因为它导致精确定时的
RGCs的退化。与人类一样,小鼠具有多种形态学不同的RGC亚型,
嵌入不同的神经回路,并提供不同的视觉功能。出于尚未确定的原因
虽然已经确定,但许多损伤类型不成比例地影响某些RGC亚型。了解那些
促进细胞存活对于设计改善疾病管理的策略至关重要。
本研究的目的是分析谷氨酸能NMDA受体在脑组织病理变化中的作用。
属于不同亚型的单个RGC。NMDA受体是钙超载的已知介质,
兴奋性毒性,它们的异常激活可通过多种途径导致细胞死亡。我们将采取一个
创新的方法,结合生物病理学逼真的建模,电生理学,以及谷氨酸
和钙成像,以提供RGC结构和功能变化的详细描述
遭受创伤性损伤。我们将重点关注的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的差异,
与神经元活动相关的参数对视觉缺陷和预后的贡献。
这项研究将大大促进我们对神经元参与的机制的理解。
对损害的反应。研资局将把从研究资助局的研究中汲取的经验教训加以综合,
神经元活动对损伤后存活的影响的全面理论描述,
一般化以提供对其他神经病理学状况的进一步理解。最后,我们的研究将
确定潜在的神经保护干预以保护视觉功能的新靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Alon Poleg-Polsky', 18)}}的其他基金
Novel experimental and machine learning - assisted techniques to assess receptive field functionality in the retina
新颖的实验和机器学习辅助技术来评估视网膜感受野功能
- 批准号:
10712234 - 财政年份:2023
- 资助金额:
$ 19.44万 - 项目类别:
Mechanisms of direction selectivity in starburst amacrine cells
星爆无长突细胞的方向选择性机制
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10063526 - 财政年份:2019
- 资助金额:
$ 19.44万 - 项目类别:
Mechanisms of direction selectivity in starburst amacrine cells
星爆无长突细胞的方向选择性机制
- 批准号:
10305620 - 财政年份:2019
- 资助金额:
$ 19.44万 - 项目类别:
Mechanisms of direction selectivity in starburst amacrine cells
星爆无长突细胞的方向选择性机制
- 批准号:
10533323 - 财政年份:2019
- 资助金额:
$ 19.44万 - 项目类别:
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