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Myeloid cell signaling pathways in neuroHIV

NeuroHIV 中的骨髓细胞信号通路

基本信息

批准号：
10701765
负责人：
Jennillee Wallace
金额：
$ 19.75万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701765
关键词：
AIDS dementia Activities of Daily Living Adult Affect Age Astrocytes Astrocytosis Attention Automobile Driving Autopsy Behavior Blood Cells Brain CD14 gene Cell Differentiation process Cell Lineage Cell Therapy Cell surface Cells Central Nervous System Chronic Clinical Clinical Research Cognitive Development Endothelial Cells Engraftment Exhibits Family Genetic Transcription Gliosis Glycoproteins HIV HIV Infections HIV encephalitis HIV-associated neurocognitive disorder Heterogeneity Hippocampus Homeostasis Human ITGAM gene Immune Immunologic Surveillance In Vitro Incidence Inflammation Inflammatory Interleukin-10 Interleukin-6 Knowledge Learning Ligands Link Macrophage Maintenance Mediating Microglia Motor Mus Myelogenous Myeloid Cells Names Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Neurons Neuropathogenesis Pathogenesis Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Population Predisposition Process Production Productivity Proliferating Proteins Proteomics Reporting Role Signal Pathway Signal Transduction Speed Testing Therapeutic Tissues Viral Load result antiretroviral therapy beta catenin brain cell brain tissue cell motility cell type cytokine functional plasticity gain of function humanized mouse in vivo inflammatory marker information processing inhibitor innovation loss of function member migration monocyte mouse model neuroAIDS neurogenesis neuroinflammation neuroprotection neurotoxicity novel phenotypic biomarker response single-cell RNA sequencing synaptogenesis

项目摘要

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.

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。