Myeloid cell signaling pathways in neuroHIV

项目摘要 巨噬细胞是艾滋病毒相关神经认知障碍（HAND）的核心参与者， 它们与神经炎症、神经毒性有关， 神经保护脑巨噬细胞和小胶质细胞对微- 环境信号，并显示广泛的激活状态，导致其 不同的功能角色。利用巨噬细胞进行治疗的关键障碍 益处在于我们对调节其表型的信号的有限理解， 功能我们发现了一个独特的单核细胞衍生的巨噬细胞（MDM）的子集， 由Wnt 7A调节。Wnt 7A是由神经元表达的分泌性糖蛋白， 血脑屏障的内皮细胞，在BBB发育中起核心作用， 神经发生和突触发生等等。我们报道了Wnt 7A-MDM 与M-1和M-2样MDM不同，表现出中间表型， 功能能力。我们假设巨噬细胞在分化过程中， Wnt 7A影响是神经保护性的并将降低CNS病毒载量。使用in 体外，人源化小鼠，和脑死后的临床研究，我们将定义的影响 Wnt 7A-MDM对HIV相关神经发病机制的影响（目的1），并确定 CNS中Wnt 7A水平与病理和临床 艾滋病毒的表现（目标2）。总之，这些研究将确定一个独特的途径， 驱动巨噬细胞表型和功能及其对HIV介导的 中枢神经系统失调。这种理解可以潜在地用于细胞 在HIV和/或其他神经退行性疾病的情况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.