COCAINE AND HIV1 IN CORONARY ENDOTHELIUM

产品说明：本项目将研究可卡因对冠状动脉内皮细胞（CAEC）感染HIV-1的影响。最近的关键数据表明，HIV-1感染CAEC和脑微血管内皮细胞（BMVEC）在流产的方式，导致强终止DNA合成，可卡因增加这种流产的感染与JR-FL株，和微血管内皮细胞显示调制的CD 4+，CXCR 4和CCR 5。在CAEC和BMVEC中，可卡因和HIV-1诱导IL-6和细胞粘附分子，并增加内皮通透性。这些作用可能导致微血管内皮渗漏和增加HIV-1侵入和白细胞迁移到心脏内膜。初步研究：他们先前已经证明，TNF-α和可卡因引起微血管内皮屏障，以允许HIV-1通过帕拉或跨细胞途径侵入，并且最近观察到HIV-1感染CAEC失败，导致R/U 5的逆转录，而没有进一步的逆转录步骤，但具有细胞内信号传导、IL-6诱导和细胞渗透性增加。他们指出可卡因和炎性细胞因子调节HIV-1 JR-FL的流产感染。他们假设：1）流产感染和CAEC通透性增加是由可卡因诱导IL-6和调节CXCR 4和CCR 5介导的，2）流产HIV-1感染、可卡因和IL-6的作用导致内皮屏障功能受损。具体目标：他们将确定1）可卡因对CAEC的流产感染的影响，2）可卡因对HIV-1穿过CAEC的通道和途径的影响，3）可卡因的信号传导，可卡因对IL-6的信号传导，以及可卡因，HIV-1和IL-6对CCR 5和CXCR 4表达的影响，以及4）可卡因，HIV-1和IL-6对渗透性，跨内皮电阻，和促凝血活性。

DESCRIPTION: (Adapted from Applants Abstracts) This project will examine the effects of cocaine on HIV-1 infection of coronary artery endothelial cells (CAEC). Recent pivotal data suggest that HIV-1 infects CAEC and brain microvascular endothelial cells (BMVEC) in an abortive fashion leading to strong-stop DNA synthesis, cocaine increases this abortive infection with the JR-FL strain, and microvascular endothelial cells display modulation of CD4+, CXCR4 and CCR5. In CAEC and BMVEC, cocaine and HIV-1 induce IL-6 and cell adhesion molecules, and increases endothelial permeability. These effects may lead to microvascular endothelial leaks and to increased HIV-1 invasion and leukocyte transmigration into the heart interstitium. Preliminary studies: They have previously demonstrated that TNF-alpha and cocaine cause the microvascular endothelial barriers to allow HIV-1 invasion by a para- or transcellular route and have recently observed that HIV-1 infects CAEC abortively leading to reverse transcription of R/U5 without further steps of reverse transcription but with intracellular signaling, IL-6 induction and increase in cell permeability. They have noted that cocaine and inflammatory cytokines modulate the abortive infection by HIV-1JR-FL. They hypothesize that 1) the abortive infection and increased permeability of CAEC are mediated by cocaine's induction of IL-6 and modulation of CXCR4 and CCR5, and 2) the effects of the abortive HIV-1 infection, cocaine, and IL-6 result in an impairment of endothelial barrier function. Specific Aims: They will determine 1) the effects of cocaine on the abortive infection of CAEC, 2) the effects of cocaine on passage and route of HIV-1 across CAEC, 3) cocaine's signaling, cocaine's signaling for IL-6, and the effects of cocaine, HIV-1 and IL-6 on CCR5 and CXCR4 expression, and 4) the effects of cocaine, HIV-1 and IL-6 on permeability, transendothelial electrical resistance, and procoagulant activity in CAEC.