Inhibitory regulation of microglia in glaucoma

青光眼中小胶质细胞的抑制性调节

基本信息

批准号：
8560974
负责人：
Monica L Vetter
金额：
$ 29.8万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8560974
关键词：
Acute Address Age Age related macular degeneration Animal Disease Models Animal Model Axon Axotomy Blindness Brain CX3CL1 gene Cell Survival Cells Cessation of life Chronic Communication Complex Deterioration Development Disease Disease Progression Equilibrium Event Eye Fractalkine Functional disorder Ganglion Cell Layer Gene Expression Profile Glaucoma Human Immune Inflammatory Injury Intervention Learning Ligands Light Mediating Microglia Microspheres Modeling Molecular Molecular Profiling Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Ocular Hypertension Parkinson Disease Pathology Pathway interactions Pattern Physiologic Intraocular Pressure Play Property Regulation Rest Retina Retinal Retinal Degeneration Retinal Ganglion Cells Risk Factors Role Signal Pathway Signal Transduction Staging Stress Testing Therapeutic Intervention Viral Waxes Work adeno-associated viral vector age related chemokine emergency service responder in vivo inhibitor/antagonist insight intravitreal injection mouse model mutant neuron loss neurotoxicity prevent public health relevance receptor research study response transcriptome sequencing

项目摘要

Abstract: Glaucoma is an age-related neurodegenerative disease that causes blindness due to selective deterioration and death of retinal ganglion cells (RGCs). While multiple risk factors, including elevated intraocular pressure (IOP) can contribute to glaucoma, the molecular and cellular mechanisms responsible for RGC degeneration are not known. Microglia have been implicated in multiple neurodegenerative diseases, including human glaucoma as well as various animal models of the disease. Here we investigate the fractalkine signaling pathway since it regulates communication between neurons and microglia in the CNS. We propose that disruption of this pathway contributes to enhanced microglia activation and increased degeneration of RGCs in glaucoma. Using two different animal models of glaucoma, we will first test whether disruption of fractalkine signaling increases microglia activation and/or RGC degeneration. Next, we will use adeno-associated viral delivery to increase fractalkine expression and test whether this limits microglia activation and/or is reduces RGC degeneration. Finally, to elucidate the molecular signature of microglia responses in glaucoma, we will generate a comprehensive molecular profile of microglia activation, and regulation by fractalkine signaling. The findings from this work will provide significant insight into the molecular pathways involved in glaucomatous pathology, and advance efforts to develop therapeutic interventions for slowing or preventing vision loss in glaucoma. !

抽象的：青光眼是一种与年龄相关的神经退行性疾病，由于选择性恶化而导致失明以及视网膜神经节细胞（RGC）的死亡。虽然存在多种危险因素，包括眼压升高 (IOP) 可导致青光眼，这是导致 RGC 变性的分子和细胞机制不知道。小胶质细胞与多种神经退行性疾病有关，包括人类青光眼以及该疾病的各种动物模型。在这里我们研究 fractalkine 信号传导途径，因为它调节中枢神经系统中神经元和小胶质细胞之间的通讯。我们建议该通路的破坏有助于增强小胶质细胞的激活并增加 RGC 的退化青光眼。使用两种不同的青光眼动物模型，我们将首先测试 fractalkine 是否被破坏信号传导会增加小胶质细胞激活和/或 RGC 变性。接下来，我们将使用腺相关病毒递送以增加 fractalkine 表达并测试这是否限制小胶质细胞激活和/或减少 RGC 变性。最后，为了阐明青光眼中小胶质细胞反应的分子特征，我们将生成小胶质细胞激活和 fractalkine 信号传导调节的全面分子概况。这这项工作的发现将为青光眼相关的分子途径提供重要的见解病理学，并努力开发治疗干预措施，以减缓或预防视力丧失青光眼。！