Inhibitory regulation of microglia in glaucoma

描述（由申请人提供）：青光眼是一种年龄相关的神经退行性疾病，由于视网膜神经节细胞（RGC）的选择性退化和死亡而导致失明。虽然多种风险因素，包括眼内压（IOP）升高，可导致青光眼，但RGC变性的分子和细胞机制尚不清楚。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，我们研究了fractalkine信号通路，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信。我们认为，这一途径的中断有助于增强小胶质细胞的激活和增加青光眼中RGCs的变性。使用两种不同的青光眼动物模型，我们将首先测试fractalkine信号传导的中断是否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来增加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活化的全面分子谱，并通过fractalkine信号转导进行调节。这项工作的发现将为青光眼病理学中的分子通路提供重要的见解，并推动开发减缓或预防青光眼视力丧失的治疗干预措施的努力。

DESCRIPTION (provided by applicant): 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 ito the molecular pathways involved in glaucomatous pathology, and advance efforts to develop therapeutic interventions for slowing or preventing vision loss in glaucoma.