Role of the BBB in HIV brain infection during methamphetamine abuse

 描述(申请人提供)：血脑屏障(BBB)是中枢神经系统最显著的屏障，代表着中枢神经系统和血流之间的重要界面。完整的血脑屏障由紧密连接(TJ)蛋白维持，是大脑动态平衡的重要决定因素。在药物滥用和包括艾滋病毒在内的各种病原体的脑感染期间，经常可以观察到血脑屏障的破坏。我们的重要结果表明，在接触甲基苯丙胺(METH)时，主要的TJ蛋白之一occludin会减少，而且occludin水平的降低不仅会导致BBB完整性的丧失，还会刺激HIV的复制。这项拟议的研究建立在这些令人兴奋的发现的基础上，其重点是中心假设，即冰毒引起的血脑屏障水平的脑血管变化对艾滋病毒脑感染的建立和结局具有深远的影响。在初步发现的指导下，这项应用提供了一个独特的视角，通过靶向血脑屏障来研究冰毒和艾滋病毒之间的相互作用。在目标1中，我们将评估冰毒诱导的occludin表达减少对NF-B和SP-1激活的影响，增强这些转录因子与HIV长末端重复序列(LTRs)的相互作用，从而刺激HIV复制。在目标2中，我们将研究冰毒和HIV诱导的血脑屏障破坏对神经前体细胞异常神经发生的影响，从而导致认知功能障碍的发展。目标3将侧重于基于运动的行为干预，以防止冰毒和艾滋病毒诱导的血脑屏障功能障碍和神经认知改变。拟议的研究具有很高的创新性，可能导致为临床开发新的翻译知识，并确定艾滋病毒复制的新调节机制。这一应用的完成有可能改变我们对Occludin在HIV感染中的细胞作用以及BBB在冰毒和/或HIV相关认知功能障碍发展中的作用的理解。此外，预期的结果可能也与其他具有重要脑血管成分的神经退行性疾病相关。

 DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is the most prominent barrier of the CNS and represents the essential interface between the CNS and the blood stream. The intact BBB is maintained by tight junction (TJ) proteins and is a paramount determinant of brain homeostasis. Disruption of the BBB is frequently observed during drug abuse and brain infections by various pathogens, including HIV. Our critically important results indicate that occludin, one of the major TJ proteins, is decreased upon methamphetamine (METH) exposure and that diminished occludin levels not only lead to the loss of integrity of the BBB but also stimulate HIV replication. The proposed research is built on these exciting findings by its focus on the central hypothesis that cerebrovascular alterations at the BBB level induced by METH have profound impact on establishing and outcome of the brain infection by HIV. Guided by the preliminary findings, this application offers a unique perspective on the interactions between METH and HIV via targeting the BBB. In Aim 1, we will evaluate the impact of METH-induced decrease in occludin expression on activation of NF-¿B and SP-1, enhancing interactions of this transcription factors with the HIV long-terminal repeats (LTRs) and thus stimulating HIV replication. In Aim 2, we will study the impact of METH and HIV-induced disruption of BBB on aberrant neurogenesis of neural progenitor cells resulting in the development of cognitive dysfunction. Aim 3 will focus on behavioral intervention based on exercise for protection against METH and HIV-induced BBB dysfunction and neurocognitive alterations. The proposed research is highly innovative and is likely to lead to the development of new translational knowledge for the clinic and identification of new regulatory mechanisms of HIV replication. The completion of this application has the potential to change our understanding of the cellular role of occludin in HIV infection and the role of the BBB in the development of METH and/or HIV-associated cognitive dysfunction. Furthermore, the expected results are likely to be also relevant to other neurodegenerative diseases that have significant cerebrovascular components.