Role of the BBB in HIV brain infection during methamphetamine abuse

 描述（由申请人提供）：血脑屏障（BBB）是CNS最重要的屏障，代表CNS和血流之间的重要界面。完整的BBB由紧密连接（TJ）蛋白维持，并且是脑稳态的最重要决定因素。在药物滥用和各种病原体（包括艾滋病毒）的脑感染期间经常观察到血脑屏障的破坏。我们至关重要的结果表明，闭合蛋白，一个主要的TJ蛋白，减少甲基苯丙胺（METH）曝光后，闭合蛋白水平的降低不仅导致BBB的完整性的损失，但也刺激HIV复制。拟议的研究是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METH诱导的BBB水平的脑血管改变对HIV脑感染的建立和结果具有深远的影响。在初步研究结果的指导下，该应用提供了一个独特的视角，通过靶向血脑屏障，了解METH与HIV之间的相互作用。在目标1中，我们将评估MET诱导的闭合蛋白表达减少对NF-B和SP-1活化的影响，增强这种转录因子与HIV长末端重复序列（LTR）的相互作用，从而刺激HIV复制。在目标2中，我们将研究METH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METH和HIV诱导的BBB功能障碍和神经认知改变。拟议的研究是高度创新的，可能会导致新的翻译知识的临床和识别艾滋病毒复制的新的调节机制的发展。这项申请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METH和/或HIV相关认知功能障碍发展中的作用的理解。此外，预期结果可能也与其他具有显著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.