Inhibitory regulation of microglia in glaucoma

摘要： 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 和视网膜神经节细胞（RGC）的死亡。虽然多种风险因素，包括眼内压升高 (IOP)可导致青光眼，这是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，包括人类的神经退行性疾病。 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 因为它调节CNS中神经元和小胶质细胞之间的通信。我们建议 该途径的破坏有助于增强小胶质细胞活化和增加RGC的变性， 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的破坏是否 信号传导增加小胶质细胞活化和/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活化和/或减少 RGC退化。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 产生小胶质细胞激活的综合分子谱，并通过fractalkine信号调节。的 这项工作的发现将为研究脑胶质瘤的分子途径提供重要的线索。 病理学，并推进努力开发治疗干预措施，以减缓或预防视力丧失， 青光眼 !

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. !