CNS macrophage accumulation during NeuroAIDS

描述(申请人提供)：与HIV感染相关的中枢神经系统症状可能包括认知障碍、运动障碍和行为改变。HIV相关痴呆已被证明与大脑中巨噬细胞的丰富有关。由于脑巨噬细胞仍不清楚，导致单核细胞进入大脑并积累更多单核细胞的机制仍然未知。具体目标1将研究外周血单核细胞在体外内皮单分子层的血管内皮细胞(即组织)一侧的迁移和积累。我们假设，表达CD16的单核细胞为通过内皮向组织迁移做好了准备，并且在HIV感染的脑内，表达了增加这些巨噬细胞的迁移、聚集和/或存活的分子。骨桥蛋白和其他分子将被检测它们在巨噬细胞聚集中的作用。我们假设骨桥蛋白可以利用其趋化和触觉特性来维持内皮层开口侧的CD16+单核细胞(足血管间隙)。特定目标2将直接检测在特定目标1中研究的分子在体内诱导单核细胞积累的能力。CD16+单核细胞的小鼠对应物将用于过继转移研究，在小鼠体内表达假定的脑积聚因子。我们假设，血液中CD16+单核细胞数量的增加，以及中枢神经系统中诱导迁移的单核细胞作为脑巨噬细胞积累的分子的产生，建立了一个刺激级联反应。

DESCRIPTION (provided by applicant): CNS symptoms associated with HIV infection can include cognitive impairments, motor disturbances, and behavioral changes. HIV-related dementia has been shown to correlate with macrophage abundance in the brain. The mechanisms responsible for increased entry of monocytes into the brain and their accumulation, as brain macrophages remain unknown. Specific Aim 1 will investigate the migration and accumulation of peripheral blood monocytes in the ablumenal (i.e. tissue) side of an in vitro endothelial monolayer. We hypothesize that blood monocytes expressing CD16 are primed for transendothelial migration into tissues, and that within the HIV-infected brain, molecules are expressed that increase transmigration, accumulation, and/or survival of these macrophages. Osteopontin, as well as other molecules will be examined for their role in macrophage accumulation. We hypothesize that osteopontin can function to maintain the CD16+ monocytes on the ablumenal side of the endothelial layer, (pedvascular space), utilizing its chemo- and haptotaxis properties. Specific Aim 2 will directly examine the ability of the molecules studied in Specific Aim 1 to induce monocytes accumulation in vivo. The mouse counterpart of CD16+ monocytes will be used in adoptive transfer studies into mice expressing the putative accumulation factors in the brain. We hypothesize that a stimulatory cascade is set up by the increased numbers of CD16+ monocytes in the blood, and the production of molecules in the CNS that induce accumulation of transmigrating monocytes as brain macrophages.