Inflammatory mechanisms associated with HIV-1 dementia

描述（由申请方提供）：HIV-1感染个体的认知能力进行性丧失，目前称为HIV-1相关神经认知障碍（HAND;也通常称为neuroAIDS），仍然是一个重要的临床问题。最近的研究表明，血脑屏障（BBB）的破坏在HAND的进展中起着重要作用。然而，在HIV-1感染期间调节血脑屏障的潜在机制仍然不清楚。在这种竞争性的更新，我们建议测试的假设，血脑屏障通透性是脑内皮细胞和星形胶质细胞之间的跨细胞通讯失调的结果，持久的影响HIV-1蛋白对CD 40/CD 40 L信号转导。我们的项目旨在通过定义新的细胞内信号传导靶点（如CD 40/CD 40 L轴和Sonic hedgehog（Shh）通路）来改变当前的研究和临床范式，这些靶点在调节BBB通透性以应对HIV-1感染方面发挥着潜在的关键作用，并通过使用新型抗Shh药物作为HAND的新型疗法来验证这些靶点的功能。在这里，我们打算整合一个全面的分析，由于HIV-1与新的方法，如活体多光子显微镜在人源化小鼠模型的细胞反应。在目的1中，我们将测试的假设，即CD 40/CD 40 L信号转导在体内HIV-1诱导的血脑屏障通透性中起着重要作用。目的2将检测CD 40/CD 40 L信号传导是否破坏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通路是否使小鼠对由HIV-1达特以CD 40 L依赖性方式诱导的BBB通透性具有抗性。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）通过推进科学知识和揭示HIV-1如何在感染患者中诱导CNS炎症，（2）通过促进新的方法和动物模型，以及（3）通过验证HAND的新治疗靶点，其在继发于BBB破坏的其它神经变性疾病中也是可行的。

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.