CNS macrophage accumulation during NeuroAIDS

描述（由申请人提供）：与HIV感染相关的CNS症状包括认知障碍、运动障碍和行为改变。HIV相关的痴呆症已被证明与大脑中的巨噬细胞丰度相关。负责增加单核细胞进入大脑和它们的积累的机制，如脑巨噬细胞仍然未知。特定目的1将研究外周血单核细胞在体外内皮单层的腔外（即组织）侧的迁移和蓄积。我们假设，表达CD 16的血液单核细胞是为跨内皮迁移到组织中做准备的，并且在HIV感染的大脑中，表达了增加这些巨噬细胞的迁移、积累和/或存活的分子。骨桥蛋白以及其他分子将被检查其在巨噬细胞积聚中的作用。我们假设骨桥蛋白可以发挥作用，以维持CD 16+单核细胞上的内皮层，（足血管空间）的ablumenal侧，利用其化学和haptotaxis属性。特异性目的2将直接检查特异性目的1中研究的分子诱导体内单核细胞蓄积的能力。小鼠对应的CD 16+单核细胞将用于过继转移研究，转移至在脑中表达推定蓄积因子的小鼠中。我们假设，刺激级联反应是由血液中CD 16+单核细胞数量的增加和CNS中分子的产生引起的，这些分子诱导迁移的单核细胞积累为脑巨噬细胞。

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.