BBB Protection in HIV-1 Dementia: Anti-Inflammatory effects of GSK-3beta suppres

描述(申请人提供)：血脑屏障(BBB)受损是HIV-1相关性痴呆(HAD)的潜在原因之一。在HAD患者的脑组织中观察到脑微血管紧密连接(TJ)的表达减少，表明BBB损伤。在之前的资助期间，我们证实了小二聚体G蛋白(Rho GTP酶，如RhoA)的激活在BMVEC TJ的改变中发挥了核心作用。RhoA抑制可阻止HIV-1感染的单核细胞迁移、TJ改变和血脑屏障通透性降低。我们确定了破坏屏障并增加单核细胞跨血脑屏障迁移的可溶性因子。我们认为，在缺乏白细胞渗透的区域看到的广泛的BBB损伤可能是由于激活的HIV-1感染的巨噬细胞在屏障的脑侧产生的这种小分子的影响。因此，HIV-1感染/激活的巨噬细胞分泌的促炎分子和脑内皮细胞与单核细胞之间的相互作用是导致血脑屏障异常的两个主要因素。此外，我们的初步数据表明，糖原合成酶激酶(GSK)-3？阻止BMVEC和单核细胞中Rho GTP酶的激活，减少单核细胞通过BBB的迁移，并通过激活的巨噬细胞减少炎症分子的产生，保护BBB。最近，GSK-3？由于其直接的神经保护特性，抑制剂被认为是HAD治疗的一种治疗选择。然而，GSK-3具有强大的免疫调节作用？抑制在神经退行性变中受到的关注要少得多。葛兰素史克-3？抑制作为HAD中血脑屏障损伤的抗炎治疗策略是当前提案的重点。在这一竞争的继续，我们将调查GSK-3的治疗潜力？通过解决以下问题，抑制及其抑制血脑屏障损害的机制：1)GSK-3是如何？抑制减少单核细胞跨血脑屏障的迁移？2)GSK-3？抑制抑制活化的HIV-1感染巨噬细胞分泌的促炎因子，从而减弱其对血脑屏障的影响？3)GSK-3可以吗？抑制剂通过其抗炎作用防止蜂房动物模型中的血脑屏障功能障碍？建议的工作将揭示GSK-3免疫调节作用的新机制？抑制并对改善HIV-1痴呆患者的血脑屏障功能障碍具有重要意义。

DESCRIPTION (provided by applicant): Blood-brain barrier (BBB) compromise is one of the underlying causes of HIV-1 associated dementia (HAD). Diminished expression of brain microvascular tight junctions (TJ) is observed in brain tissues of HAD patients indicating BBB injury. During the previous period of funding, we established that activation of small dimeric G-proteins (Rho GTPases, such as RhoA) played a central role in alterations of BMVEC TJ. RhoA inhibition prevented migration of HIV-1 infected monocytes, TJ changes and diminished permeability of the BBB. We identified soluble factors that disrupted the barrier and increased monocyte migration across the BBB. We believe that widespread BBB injury seen in areas devoid of leukocyte infiltration could be due to effects of such small molecules produced by activated HIV-1 infected macrophages on the brain side of the barrier. Thus, pro-inflammatory molecules secreted by HIV-1 infected/activated macrophages and interactions between brain endothelial cells and monocytes are two major factors contributing to BBB abnormalities. In addition, our preliminary data indicated that inhibition of glycogen synthase kinase (GSK)-3? prevented activation of Rho GTPases in BMVEC and monocytes, decreased monocyte migration through the BBB and reduced production of inflammatory molecules by activated macrophages, preserving BBB. Recently, GSK-3? inhibitors were recognized as a therapeutic option for HAD treatment due to their direct neuroprotective properties. However, powerful immunomodulatory effects of GSK-3? inhibition have received much less attention in neurodegeneration. GSK-3? suppression as an anti-inflammatory treatment strategy for BBB injury in HAD is the focus of the current proposal. In this competing continuation, we will investigate the therapeutic potential of GSK-3? inhibition and the mechanisms through which it can curtail BBB compromise by addressing the following questions: 1) How GSK-3? inhibition diminishes monocyte migration across the BBB? 2) Can GSK-3? suppression decrease secretion of pro-inflammatory factors in activated HIV-1 infected macrophages attenuating their effects on the BBB? and 3) Can GSK-3? inhibitors prevent BBB dysfunction in an animal model for HIVE via their anti-inflammatory effects? The proposed works will uncover novel mechanisms underlying the immunomodulatory effects of GSK-3? suppression and are highly significant for amelioration of BBB dysfunction in HIV-1 dementia.