CNS macrophage accumulation during NeuroAIDS

点击翻译按钮获取中文摘要

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.