CNS macrophage accumulation during NeuroAIDS

描述（由申请人提供）：与HIV感染相关的中枢神经系统症状包括认知障碍、运动障碍和行为改变。hiv相关的痴呆已被证明与大脑中巨噬细胞的丰度相关。单核细胞作为脑巨噬细胞增加进入大脑及其积累的机制尚不清楚。特异性目的1将研究外周血单核细胞在体外内皮单层的腔内（即组织）侧的迁移和积累。我们假设，表达CD16的血液单核细胞可经内皮细胞迁移到组织中，并且在hiv感染的大脑中，表达的分子可增加这些巨噬细胞的迁移、积累和/或存活。骨桥蛋白以及其他分子在巨噬细胞积聚中的作用将被研究。我们假设骨桥蛋白可以利用其趋化性和亲合性来维持内皮层（血管间隙）腔侧的CD16+单核细胞。特异性Aim 2将直接检测特异性Aim 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，用于表达大脑中假定的积累因子的小鼠。我们假设刺激级联是由血液中CD16+单核细胞数量的增加和CNS中诱导迁移单核细胞作为脑巨噬细胞积累的分子的产生而建立的。

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.