Macrophage, blood-brain barrier, and modulation of neurodegeneration

虽然血脑屏障(BBB)受损是HIV-1神经发病机制的一个关键特征，但BBB还 作为治疗学大脑传递的管道。这与血脑屏障的病理生理学如何相交是焦点。 当前项目的。目前公认的事实是，神经前体细胞(NPC)动态地 对出生后大脑的神经和神经胶质形成做出贡献，并在该计划拨款中得到开发 (项目1，郑俊杰)。作为对损伤、感染或神经退化的反应，祖细胞迁移到 组织损伤区。与神经炎性反应相关产生的趋化因子可能起作用 在脑损伤期间作为神经前体细胞的化学诱导剂。鼻咽癌是否从血中跨越血脑屏障 目前仍不清楚。我们认为系统性鼻咽癌可以跨血脑屏障迁移并促进 在减轻HIV-1脑炎(HIVE)神经炎症的同时进行神经保护。我们会研究 鼻咽癌迁移机制及其对血脑屏障影响的病理生理学研究 神经炎症中趋化因子过度产生的假设。我们将调查跨国迁移如何 血脑屏障改变鼻咽癌分化为神经元和胶质细胞的方式以及鼻咽癌对血脑屏障的影响 大脑。该计划赠款中的战略正在制定，以实现广泛的抗逆转录病毒 将艾滋病毒-1病毒的辅助药物包装成纳米颗粒(NP；项目2，H.Gendelman)。 这些细胞可以被白细胞摄取，并被输送到活跃的神经炎症区域。在成为一名 有吸引力的促进抗逆转录病毒或抗炎药物输送的具体方式，目前尚不清楚 含NP的白细胞在迁移过程中或从屏障的“脑”侧影响血脑屏障功能 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，我们将解决 巨噬细胞在载药NP的血脑屏障中迁移的途径和纳米毒理学。我们会 评估细胞的移动能力，影响血脑屏障的完整性和功能，并影响与疾病相关的 神经病理学。这些基于细胞的新治疗方法是跨学科的，并显示出 各项目之间的关系(NPC项目1，J.郑NP--药物交付项目2，H. Gendelman)拥有我们在BBB模型方面的成熟专业知识。重要的是，三种不同的动物模型 将使用体内成像技术来验证体外观察，从而 评估血脑屏障完整性、神经元损伤和神经炎症。

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.