microRNA-124 restores nerurogenesis in HIV-1 associated neurocognitve disorders

描述：与HIV-1相关的神经系统疾病影响40-70%的感染者，其特征是： HIV-1相关的神经认知障碍（HAND）。虽然抗逆转录病毒疗法（ART）减轻了疾病的严重程度，但轻度的认知障碍仍然很常见。因此，寻找新的治疗策略以全面预防神经认知功能障碍至关重要。活跃的神经发生发生在整个生命过程中，并依赖于神经干/祖细胞（NPC）的增殖，迁移和适当分化。在与神经炎症（例如HAND）相关的中枢神经系统（CNS）病理条件下，浸润中枢神经系统的单核细胞/巨噬细胞与活化的驻留小胶质细胞一起在HAND的神经退行性过程中发挥重要作用。活化的巨噬细胞/小胶质细胞产生炎症介质，如细胞因子和趋化因子，影响脑干细胞的能力并改变神经发生。各种类型的巨噬细胞/小胶质细胞活化，取决于条件，可以增强或抑制神经发生。炎症相关的M1巨噬细胞/小胶质细胞可以抑制神经发生;而IL-4激活的M2巨噬细胞/小胶质细胞可以诱导神经发生和少突胶质细胞发生。在HAND中，大脑中的HIV-1感染抑制神经发生，在海马齿状回中产生较少的成年NPC。此外，NPC优选分化成星形胶质细胞而不是神经元。我们以前的研究表明，HIV-1感染和LPS激活（M1）的巨噬细胞抑制神经发生，同时通过分泌炎性细胞因子如IL-1 β和TNF-α来促进胶质细胞的生成。microRNA- 124（miR-124）最近已显示使M1巨噬细胞失活并使它们的极化从M1向M2表型偏斜。miR-124可以作为一种有用的工具，将有害的促炎性M1巨噬细胞/小胶质细胞转移到有益的M2巨噬细胞/小胶质细胞。因此，我们提出了以下具体目标：目的1：研究miR-124如何灭活HIV-1感染的M1巨噬细胞/小胶质细胞或将其极化为M2表型并促进体外神经发生。目标二：研究miR-124改善HIV-1脑炎（HIVE）和人源化小鼠模型中HIV-1感染介导的神经发生抑制的治疗潜力。我们将使用原代人NPC、巨噬细胞/小胶质细胞培养系统以及HIVE和人源化小鼠模型来检验我们的假设。这种新的系统模拟HIV-1感染和脑巨噬细胞/小胶质细胞的免疫激活，因为它们在HAND期间发生在CNS内。我们将在体外和体内验证miR-124对调节巨噬细胞/小胶质细胞活化的作用及其随后对神经发生的作用。从这项研究中产生的数据将有助于确定一个高度创新的策略手治疗。此外，这些发现将提供一系列其他神经退行性和神经炎症性疾病的见解，其中巨噬细胞/小胶质细胞活化起着重要作用。

DESCRIPTION: Neurological disorders associated with HIV-1 affect 40-70% of infected individuals and is characterized as HIV-1-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) has diminished disease severity, milder forms of cognitive impairment remain commonplace. It is critical to discover new therapeutic strategies to fully prevent the neurocognitive impairment. Active neurogenesis occurs throughout life and relies upon the proliferation, migration, and proper differentiation of neural stem/progenitor cells (NPCs). Under pathological conditions of the central nervous system (CNS) associated with neuroinflammation such as HAND, monocytes/macrophages infiltrating the CNS in concert with activated resident microglia play a major role in the neurodegenerative process of HAND. Activated macrophage/microglia produce inflammatory mediators such as cytokines and chemokines, affect the capacity of brain stem cells and alter neurogenesis. Various types of macrophage/microglia activation, depending on the conditions, can either enhance or suppress neurogenesis. Inflammation-associated M1 macrophages/microglia can inhibit neurogenesis; whereas IL-4-activated M2 macrophages/microglia can induce both neurogenesis and oligodendrogenesis. In HAND, HIV-1 infection in the brain inhibits neurogenesis with generation of fewer adult NPCs in the dentate gyrus of the hippocampus. Moreover, NPCs preferably differentiate into astrocytes rather than neurons. Our previous studies demonstrated HIV-1-infected and LPS-activated (M1) Macrophages inhibit neurogenesis, while enhancing gliogenesis through secretion of inflammatory cytokines such as IL-1ß and TNF-α. microRNA- 124 (miR-124) has recently been shown to deactivate M1 macrophages and skew their polarization from an M1 toward an M2 phenotype. miR-124 may serve as a useful tool to transfer detrimental pro-inflammatory M1 macrophages/microglia to beneficial M2 macrophages/microglia. Therefore, we propose the following specific aims: Aim 1: To investigate how miR-124 deactivates HIV-1-infected M1 macrophages/microglia or polarizes them to an M2 phenotype and promotes neurogenesis in vitro. Aim 2: To investigate the therapeutic potential of miR-124 for ameliorating HIV-1-infection-mediated inhibition of neurogenesis in HIV-1 encephalitis (HIVE) and humanized mouse models. We will test our hypothesis using primary human NPC, macrophage/microglia culture systems, and HIVE and humanized mouse models. This novel system mimics the HIV-1-infection and immune-activation of brain macrophage/microglia as they occur within the CNS during HAND. We will validate the effect of miR-124 on modulating macrophage/microglia activation and its subsequent effect on neurogenesis in vitro and in vivo. The data generated from this study will help to identify a highl innovative strategy for HAND therapy. Furthermore, these findings will provide insight into a range of other neurodegenerative and neuroinflammatory diseases in which macrophage/microglia activation plays an important role.