The role of microglia in experimental glaucoma

描述(申请人提供)：青光眼是一种与年龄相关的神经退行性疾病，全世界有多达6000万人受到影响。视神经轴突进行性恶化和视网膜神经节细胞(RGC)选择性死亡是视野丧失和失明的主要原因。眼压升高是青光眼的危险因素，但不足以导致疾病，提示其他共谋事件会导致视轴突进性下降、RGC活性丧失和最终细胞凋亡。青光眼中RGC变性的确切机制尚不清楚。在这项研究中，我们研究了小胶质细胞和补体通路在DBA/2J青光眼模型视网膜神经节细胞衰退中的作用。小胶质细胞是中枢神经系统的常驻免疫监视细胞，对神经元应激和损伤非常敏感，并与多种神经退行性疾病有关。有证据表明，在人类青光眼和各种动物模型中，小胶质细胞被激活，但小胶质细胞激活在青光眼中的后果尚不清楚。在这项提案中，我们将记录小胶质细胞激活和RGC下降之间的关系。然后，我们将诱导性地耗尽视网膜中的小胶质细胞，或抑制视网膜中的补体途径，并评估其对RGC退化的影响。这项研究将首次详细研究小胶质细胞激活和补体表达在青光眼动物模型中的功能后果。这项工作的发现可能成为测试针对人类青光眼小胶质细胞或补体通路的治疗干预的基础。 公共卫生意义：青光眼是一种毁灭性的眼部神经退行性疾病，是世界范围内导致失明的主要原因。参与疾病进展的细胞和分子参与者只被部分了解，限制了为疾病开发新的创新治疗方法的能力。这项提议中的实验将扩展关于小胶质细胞和天然免疫途径在青光眼中所起作用的知识。这可能揭示潜在的候选生物标记物以及治疗干预的新靶点。

DESCRIPTION (provided by applicant): Glaucoma is an age-related neurodegenerative disease that affects up to 60 million people worldwide. Visual field loss and blindness result from progressive deterioration of the optic axons and selective death of retinal ganglion cells (RGCs). Intraocular pressure (IOP) elevation constitutes a risk factor in glaucoma, but is not sufficient to cause disease, suggesting that other conspiring events lead to progressive decline of optic axons, loss of RGC viability and final apoptosis. The exact mechanism responsible for RGC degeneration in glaucoma is not known. In this proposal we investigate the role of microglia and complement pathways in retinal ganglion cell decline in the DBA/2J model of glaucoma. Microglia, the resident immune surveillance cells of the CNS, are exquisitely sensitive to neuronal stress and injury, and have been implicated in multiple neurodegenerative diseases. There is evidence that microglia become activated in human glaucoma as well as in various animal models, however the consequences of microglial activation in glaucoma remains unknown. In this proposal we will document the relationship between microglia activation and RGC decline. We will then inducibly deplete microglia from the retina, or inhibit complement pathways in the retina, and assess the effects on RGC degeneration. This study will provide the first detailed investigation of the functional consequences of microglia activation and complement expression in an animal model of glaucoma. The findings from this work may form the basis for testing therapeutic interventions targeting microglia or complement pathways in human glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is a devastating neurodegenerative disease of the eye, and is a leading cause of blindness worldwide. The cellular and molecular players involved in disease progression are only partially understood, limiting the ability to develop new innovative treatments for the disease. The experiments in this proposal will extend the knowledge about the role of microglia and innate immunity pathways in glaucoma. This may reveal potential candidate biomarkers for the disease as well as novel targets for therapeutic intervention.