Inflammatory mechanisms associated with HIV-1 dementia

描述(由申请人提供)：HIV-1感染者认知能力的进行性丧失，目前被称为HIV-1相关性神经认知障碍(HAND；也被普遍称为神经艾滋病)，仍然是一个重大的临床问题。最近的研究表明，血脑屏障(BBB)的破坏在手部疾病的发展中起着重要作用。然而，在HIV-1感染过程中调节血脑屏障的潜在机制仍然不清楚。在这一竞争性更新中，我们建议检验这一假设，即血脑屏障通透性是脑内皮细胞和星形胶质细胞之间放松调节的跨细胞通讯的结果，遵循HIV-1蛋白对CD40/CD40L信号的持久影响。我们的项目试图通过定义新的细胞内信号靶点，如CD40/CD40L轴和Sonic hedgehog(Shh)途径，在调节HIV-1感染反应中的血脑屏障通透性方面发挥潜在的关键作用，并通过使用新型抗Shh药物作为新的手部疗法对这些靶点进行功能验证，从而改变当前的研究和临床范式。在这里，我们打算将对HIV-1引起的细胞反应的全面分析与新的方法相结合，例如在人源化小鼠模型中的活体多光子显微镜。在目标1中，我们将验证CD40/CD40L信号在HIV-1诱导的体内血脑屏障通透性中起重要作用的假设。AIM 2将研究CD40/CD40L信号是否干扰星形胶质细胞和脑内皮细胞之间的跨细胞通讯。最后，在目标3中，我们将研究靶向Shh途径是否使小鼠以CD40L依赖的方式抵抗HIV-1 Tat诱导的血脑屏障通透性。这些研究的结果预计将在三个方面对神经艾滋病领域产生重大影响：(1)通过促进科学知识和揭示HIV-1如何在感染患者中诱导中枢神经系统炎症，(2)通过促进新的方法和动物模型，以及(3)通过验证新的手部治疗靶点，这些靶点也适用于其他继发于血脑屏障中断的神经退行性疾病。

DESCRIPTION (provided by applicant): The progressive loss of cognitive abilities in HIV-1-infected individuals, which is currently referred to as HIV-1-associated neurocognitive disorders (HAND; also popularly known as neuroAIDS), remains a substantial clinical concern. Recent studies have shown that the disruption of the blood-brain barrier (BBB) plays a major role in the progression of HAND. However, the underlying mechanisms that regulate the BBB during HIV-1 infection remain poorly defined. In this competitive renewal, we propose to test the hypothesis that BBB permeability is the result of deregulated trans-cellular communication between brain endothelial cells and astrocytes, following enduring effects of HIV-1 proteins on CD40/CD40L signaling. Our project seeks to shift current research and clinical paradigms by defining novel intracellular signaling targets, such as the CD40/CD40L axis and the Sonic hedgehog (Shh) pathway, that play potentially crucial roles in regulating BBB permeability in response to HIV-1 infection, and through functional validation of these targets by using novel anti-Shh drugs as novel therapeutics for HAND. Here we intend to integrate a comprehensive analysis of cellular responses due to HIV-1 with novel methodologies such as intravital multiphoton microscopy in a humanized mouse model. In Aim 1, we will test the hypothesis that CD40/CD40L signaling plays an important role in HIV-1-induced BBB permeability in vivo. Aim 2 will examine whether CD40/CD40L signaling disrupts trans-cellular communication between astrocytes and brain endothelial cells. Finally, in Aim 3 we will investigate whether targeting the Shh pathway renders mice resistant to BBB permeability induced by HIV-1 Tat in a CD40L-dependent manner. The results obtained in these studies are expected to exert a high impact on the neuroAIDS field on three counts: (1) by advancing scientific knowledge and revealing how HIV-1 induces CNS inflammation in infected patients, (2) by promoting novel methodologies and animal models, and (3) by validating novel therapeutic targets for HAND, which are also viable in other neurodegenerative disorders that are secondary to BBB disruption.