The role of microglia in experimental glaucoma

描述（由申请人提供）：青光眼是一种与年龄相关的神经退行性疾病，影响全球多达6000万人。视野丧失和失明是视轴突进行性恶化和视网膜神经节细胞（RGCs）选择性死亡的结果。眼压升高是青光眼的一个危险因素，但并不足以导致青光眼发病，提示其他因素导致视轴突进行性下降、RGC活力丧失和最终细胞凋亡。青光眼RGC变性的确切机制尚不清楚。在本研究中，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下降中的作用。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，小胶质细胞在人类青光眼以及各种动物模型中被激活，然而，小胶质细胞在青光眼中的激活后果尚不清楚。在这个提议中，我们将证明小胶质细胞激活和RGC下降之间的关系。然后，我们将诱导耗尽视网膜中的小胶质细胞，或抑制视网膜中的补体通路，并评估对RGC变性的影响。本研究将首次详细研究青光眼动物模型中小胶质细胞激活和补体表达的功能后果。这项工作的发现可能为测试针对人类青光眼的小胶质细胞或补体通路的治疗干预奠定基础。

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.