The Axon-Oligodendrocyte Precursor Synapse in NeuroAIDS

描述（由申请人提供）：本R21申请是对RFA-MH-08-031“HIV神经发病机制：新出现的国内和全球问题，“将研究自高效抗逆转录病毒治疗（HAART）以来，与中枢神经系统HIV-1感染相关的神经系统疾病的盈亏表型的分子机制。已经成为治疗的主流神经心理学和神经学评估表明，认知和运动缺陷的波动模式，部分定位于胼胝体，并不一定在一个不可阻挡的逐步下降的模式，这将表明不可挽回的结构损伤和细胞死亡，在这些途径。对HIV-1感染和神经系统疾病患者的扩散张量成像（DTI）神经放射学研究以及对HIV/SIV感染的人和猴脑组织的免疫细胞化学研究结果表明，胼胝体中的白色物质功能和轴突结构异常。相反，HIV-1直接感染体内少突胶质细胞或其细胞死亡的证据仍然存在争议。虽然研究表明HIV-1达特或gp 120与少突胶质细胞功能障碍有关，但其机制仍不明确。在这里，我们将集中在达特，由于其独特的能力，调节突触传递，以及启动招聘和激活的单核细胞在中枢神经系统放大其神经毒性。作为理解神经状态波动变化的第一步，这在一定程度上与胼胝体损伤有关，我们将通过研究HIV-1达特如何直接或间接损害与轴突突触通讯的少突胶质细胞前体细胞，并损害胼胝体中的轴突传导，来模拟体内胼胝体功能障碍。这种类型的突触的特征在于兴奋性神经递质谷氨酸从轴突的活性依赖性囊泡释放，并且可以在表达膜蛋白聚糖NG 2（NG 2+）的[突触后]少突胶质细胞祖细胞（OPC）中诱导离子流，并最终分化成少突胶质细胞。我们进一步假设，达特可以招募浸润的血管周围巨噬细胞，加剧对OPC池的损害，最终影响OPC促进维持正常胼胝体结构和功能的成熟少突胶质细胞群体的能力。为了验证这些假设，在目标1中，我们将研究HIV-1达特和浸润的血管周围巨噬细胞如何影响OPC池和胼胝体结构的生命周期，在目标2中，我们将研究HIV-1达特如何改变胼胝体轴突和OPC之间的通讯，并研究这是否反过来损害完整脑切片中的轴突传导。这些实验的数据将进一步了解轴突-OPC突触组件的损伤是否有助于HIV-1相关的神经系统疾病，并可能代表一个以前未确定的治疗靶点。

DESCRIPTION (provided by applicant): This R21 application, in response to RFA-MH-08-031, "Mechanisms of HIV Neuropathogenesis: Emerging Domestic and Global Issues," will investigate the molecular mechanisms that give rise to the waxing and waning phenotype of neurologic disease associated with HIV-1 infection of the central nervous system in the years since highly active antiretroviral therapy (HAART) has become the mainstay of therapy. Neuropsychologic and neurologic evaluations demonstrate fluctuant patterns of cognitive and motor deficits that localize in part to the corpus callosum and do not necessarily proceed in an inexorable stepwise pattern of decline that would suggest irrevocable structural damage and cell death in these pathways. Results from diffusion tensor imaging (DTI) neuroradiologic studies of patients with HIV-1 infection and neurologic disease, as well as immunocytochemical studies from human and monkey brain tissue with HIV/SIV infection demonstrate abnormalities in white matter function and axonal structure in the corpus callosum. In contrast, evidence for direct HIV-1 infection of oligodendrocytes in vivo or their cell death remains controversial. While studies have implicated HIV-1 Tat or gp120 in oligodendrocyte dysfunction, the mechanisms for this remain undefined. Here, we will focus on Tat due to its unique ability to modulate synaptic transmission, as well as initiate recruitment and activation of mononuclear cells in the CNS to amplify its neurotoxicity. As a first step in understanding fluctuant changes in neurologic status that are referable in part to damage to the corpus callosum, we will model dysfunction of the corpus callosum in vivo by investigating how HIV-1 Tat may directly or indirectly damage oligodendrocyte precursor cells that are in synaptic communication with axons, and impair axonal conduction in the callosum. This type of synapse is characterized by activity-dependent vesicular release of the excitatory neurotransmitter glutamate from axons and can induce ionotropic currents in [post-synaptic] oligodendrocyte progenitor cells (OPCs) that express the membrane proteoglycan NG2 (NG2+), and ultimately differentiate into oligodendrocytes. We further hypothesize that Tat can recruit infiltrating perivascular macrophages to exacerbate damage to OPC pools, ultimately affecting the ability of OPC to contribute to the population of mature oligodendrocytes that maintains normal callosal structure and function. To test these hypotheses, in aim 1, we will investigate how HIV-1 Tat and infiltrating perivascular macrophages can affect the life cycle of OPC pools and callosal structure and in aim 2, we will investigate how HIV-1 Tat can alter communication between callosal axons and OPCs and investigate whether this in turn impairs axonal conduction in intact brain slices. Data from these experiments will further our understanding of whether damage to components of the axon-OPC synapse contributes to HIV-1 associated neurologic disease and may represent a previously unidentified therapeutic target.