Myeloid cell signaling pathways in neuroHIV

项目摘要 巨噬细胞是HIV相关神经认知障碍(HAND)的核心参与者， 它们与神经炎症、神经毒性有关，有时还与 神经保护。脑巨噬细胞和小胶质细胞对微血管信号敏感。 环境信号并显示广泛的激活状态，从而导致其 不同的职能角色。利用巨噬细胞进行治疗的关键障碍 好处在于我们对调节其表型的信号了解有限 功能。我们鉴定了一组独特的单核细胞来源的巨噬细胞(MDM) 受WNT7A调控。WNT7A是一种分泌型糖蛋白，由神经元和 血脑屏障的内皮细胞，在血脑屏障的发育中起着中心作用， 神经发生和突触发生，不一而足。我们报告了WNT7A-MDM 与M-1和M-2类似的MDM不同，并表现出中间表型和 功能能力。我们假设巨噬细胞在 Wnt7A的影响具有神经保护作用，可降低中枢神经系统病毒载量。使用中 体外、人源化小鼠和大脑死后临床研究我们将定义这种影响 Wnt7A-MDMS对HIV相关神经致病作用的研究(目标1)，并确定 中枢神经系统Wnt7A水平与病理和临床的关系 艾滋病毒的表现(目标2)。总之，这些研究将定义一条独特的路径 巨噬细胞的表型和功能及其对HIV介导的影响 中枢神经系统的调节失调。这一理解有可能被用于细胞 艾滋病毒和/或其他神经退行性疾病背景下的治疗性神经保护。

Project Summary Macrophages are central players in HIV-Associated Neurocognitive Disorders (HAND), where they are implicated in neuroinflammation, neurotoxicity, and at times in neuroprotection. Brain macrophages and microglia are sensitive to signals to micro- environmental signals and display a wide range of activation states resulting in their different functional roles. A critical barrier to harnessing macrophages for therapeutic benefit lies in our limited understanding of the signals that regulate their phenotype and function. We identified a unique subset of monocyte derived macrophages (MDMs) regulated by Wnt7A. Wnt7A is a secreted glycoprotein expressed by neurons and endothelial cells of the blood brain barrier, with central roles in BBB development, neurogenesis, and synaptogenesis, to a name a few. We reported that Wnt7A-MDMs are distinct from M-1 and M-2 like MDMs and exhibit an intermediate phenotype and functional capacity. We hypothesize that macrophages differentiated under the influence of Wnt7A are neuroprotective and will decrease CNS viral load. Using in vitro, humanized mice, and brain post-mortem clinical studies we will define the impact of Wnt7A-MDMs on HIV-associated neuropathogenesis (Aim 1) and determine the association between Wnt7A levels in the CNS and the pathologic and clinical manifestation of HIV (Aim 2). Together, these studies will define a unique pathway driving macrophage phenotype and function and its impact on HIV-mediated dysregulation in the CNS. This understanding can potentially be harnessed for cellular therapeutic neuroprotection in context of HIV and/or other neurodegenerative diseases.