Macrophage, blood-brain barrier, and modulation of neurodegeneration

虽然血脑屏障（BBB）损伤是HIV-1神经发病机制的关键特征，但BBB也 用作治疗剂脑递送的管道。这是如何与血脑屏障病理生理学交叉的焦点 目前的项目。神经前体细胞（NPC）动态分化是一个公认的事实， 有助于出生后大脑中的神经元和神经胶质细胞的生成，并在该项目资助下正在开发 （项目1，J.Zheng）。作为对损伤、感染或神经退行性变的反应，祖细胞迁移到 组织损伤区域。与神经炎症反应相关的趋化因子可能起作用 作为脑损伤期间神经祖细胞的化学引诱物。NPC是否通过血脑屏障 仍不清楚我们认为，系统性NPC可以迁移穿过BBB，并促进 在HIV-1脑炎（HIVE）中，神经保护同时减轻神经炎症。我们将研究 使用病理生理学相关的方法，研究NPC迁移的机制及其对BBB的影响。 神经炎症中趋化因子过度产生的假设。我们将调查如何跨越 血脑屏障改变了NPC分化为神经元和胶质细胞的方式，以及NPC从脑内对血脑屏障的影响。 个脑袋该计划赠款的战略正在制定，使广谱抗逆转录病毒治疗成为可能。 以及将HIV-1的预防性药物包装成纳米颗粒（NP;项目2，H. Gendelman）。 这些可以被白细胞摄取并转运到活跃的神经炎症区域。虽然作为一个 有吸引力的具体方式，以促进抗逆转录病毒或抗炎药物的输送，它目前是未知的 含NP的白细胞在迁移过程中或从屏障的"脑"侧如何影响BBB功能， 也许更重要的是它们如何影响神经元和神经胶质的完整性。因此，我们将处理 途径和纳米毒理学的巨噬细胞迁移通过血脑屏障与载药的NP。我们将 评估细胞移动和影响BBB的完整性和功能的能力，以及影响疾病相关性的能力。 神经病理学这些基于细胞的新型治疗方法是跨学科的， 项目间的协同（NPC项目1，J.Zheng和NP-药物递送项目2，H. Gendelman）拥有我们自己在BBB模型方面的专业知识。重要的是，三种不同的动物模型 将采用体内成像技术验证体外观察结果， BBB完整性、神经元损伤和神经炎症的评估。

While blood brain barrier (BBB) impairment is a critical feature of HIV-1 neuropathogenesis, the BBB also serves as a conduit for therapeutics brain delivery. How this intersects with BBB pathophysiology is the focus of the current project. It is a now well-established fact that neural progenitor cells (NPC) dynamically contribute to neuro- and gliogenesis in the postnatal brain and are being developed in this program grant (project 1, J. Zheng). In response to injury, infection, or neurodegeneration, progenitor cells migrate toward zones of tissue damage. Chemokines produced in association with neuroinflammatory responses likely act as chemoattractants for neural progenitors during brain injury. Whether NPC cross the BBB from blood remains unclear. We propose that systemic NPC can migrate across the BBB and promote neuroprotection while attenuating neuroinflammation in HIV-1 encephalitis (HIVE). We will study mechanisms governing NPC migration and their effect on the BBB using the pathophysiologically relevant assumption of chemokine overproduction in neuroinflammation. We will investigate how migration across the BBB alters how NPC differentiate into neurons and glia and the effects of NPC on the BBB from within the brain. Strategies in this program grant are being developed that enable a broad spectrum of anti-retroviral and adjunctive medicines for HIV-1 to be packaged into nanoparticles (NP; project 2, H. Gendelman). These can be taken by leukocytes and transported into areas of active neuroinflammation. While being an attractive specific way to facilitate anti-retroviral or anti-inflammatory drug delivery, it is currently unknown how NP-containing leukocytes affect BBB function during migration or from the 'brain' side of the barrier and perhaps even more importantly how they affect neuronal and glial integrity. Therefore, we will address the pathways and nanotoxicology for migration of macrophages across BBB with drug laden NP. We will evaluate the cell's ability to move and affect the integrity and function of the BBB and to affect diseaserelated neuropathology. These cell-based novel therapeutic approaches are interdisciplinary and show ynergy amongst the projects (NPC project 1, J. Zheng and NP-delivery of drugs project 2, H. Gendelman) with our own established expertise in BBB models. Importantly, three diverse animal models for HIVE will be employed to validate in vitro observations using in vivo imaging techniques allowing assessment of BBB integrity, neuronal injury, and neuroinflammation.