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神经轴突进行性退化和视网膜神经节细胞（RGC）选择性死亡的结果。眼内压（IOP）升高构成青光眼的危险因素，但不足以引起疾病，这表明其他共同事件导致视神经轴突的进行性衰退，RGC活力丧失和最终凋亡。青光眼中RGC变性的确切机制尚不清楚。在这个提议中，我们研究了小胶质细胞和补体途径在青光眼DBA/2 J模型中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，然而青光眼中小胶质细胞激活的后果仍然未知。在本提案中，我们将记录小胶质细胞激活和RGC下降之间的关系。然后，我们将诱导性地从视网膜中耗尽小胶质细胞，或抑制视网膜中的补体途径，并评估对RGC变性的影响。这项研究将提供第一个详细的调查功能的后果，小胶质细胞激活和补体表达的青光眼动物模型。这项工作的发现可能成为测试针对人类青光眼中小胶质细胞或补体通路的治疗干预的基础。 公共卫生相关性：青光眼是一种毁灭性的眼部神经退行性疾病，是全球失明的主要原因。参与疾病进展的细胞和分子参与者仅部分了解，限制了开发新的创新治疗方法的能力。本研究的实验结果将有助于进一步认识小胶质细胞和先天免疫通路在青光眼发病中的作用。这可能揭示疾病的潜在候选生物标志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.