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

描述（由申请人提供）：血脑屏障（BBB）受损是HIV-1相关痴呆（HAD）的根本原因之一。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，我们确定了小的二聚G蛋白（Rho GTP酶，如RhoA）的激活在BMVEC TJ的改变中起着核心作用。RhoA抑制阻止了HIV-1感染的单核细胞的迁移、TJ变化和BBB通透性降低。我们确定了破坏屏障和增加单核细胞迁移通过血脑屏障的可溶性因子。我们认为，在没有白细胞浸润的区域中观察到的广泛的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，由HIV-1感染/活化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促成BBB异常的两个主要因素。此外，我们的初步数据表明，抑制糖原合成酶激酶（GSK）-3？阻止BMVEC和单核细胞中Rho GTP酶的活化，减少单核细胞通过BBB的迁移，并减少活化的巨噬细胞产生的炎性分子，保护BBB。最近，GSK-3？抑制剂由于其直接的神经保护特性而被认为是HAD治疗的治疗选择。然而，强大的免疫调节作用的GSK-3？抑制在神经变性中受到较少关注。GSK-3？抑制作为HAD中BBB损伤的抗炎治疗策略是当前提案的焦点。在这个竞争的延续，我们将调查GSK-3的治疗潜力？通过解决以下问题，研究GSK-3的抑制作用及其减少BBB损害的机制：1）GSK-3如何？抑制减少单核细胞迁移通过血脑屏障？2)GSK-3可以吗？抑制减少激活的HIV-1感染的巨噬细胞中促炎因子的分泌，减弱其对BBB的影响？GSK-3能吗？抑制剂通过抗炎作用预防HIVE动物模型中的BBB功能障碍？拟议的工作将揭示GSK-3的免疫调节作用的新机制？抑制，并对改善HIV-1痴呆中的BBB功能障碍具有高度意义。

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.