Signaling Pathways Modulating HIV-1 Induced Injury in CNS

调控HIV-1诱导中枢神经系统损伤的信号通路 这个相互竞争的更新计划项目的中心目标和目标仍然是利用多学科方法来破译在HIV-1感染时调节脑细胞损伤发展的分子信号事件。HIV-1感染脑小胶质细胞、血管周围巨噬细胞以及星形胶质细胞，导致病毒和细胞因子的分泌，引起慢性炎症，触发信号转导，诱导氧化应激。所有这些事件都会影响#年HIV-1的整体复制 被感染的细胞通过一系列复杂的细胞质反应，将信号传递到未感染细胞的细胞核，如神经元，从而导致基因导向的神经元死亡和凋亡。在这项研究计划中，我们将使用许多分子、遗传学、病毒学和神经病理学方法来发起真正的多学科努力，以了解与脑内HIV-1感染的神经致病相关的信号事件。因此，这个项目的中心主题是通过关注Tat等病毒蛋白之间的相互作用来研究HIV-1与CNS的相互作用 和VPR，以及控制寄主内稳态的寄主信号通路。在项目1中，我们将通过关注Rho GTP酶来研究TAT在诱导神经细胞功能障碍中的作用，Rho GTP酶是神经细胞分化和存活中最有影响力的生物途径之一。在项目2中，我们将检验这样的假设，即神经元突起的退化是由TNFa诱导的IGF信号通路的关键成分磷酸化的IRS-1与导致收缩的整合素之间的相互作用引起的 神经突起的特征。最后，在项目#3中，我们将研究HIV-1感染对缺氧诱导因子1(HIF-1)等氧化应激因子的影响，以及HIF-1和VPR在支持脑内HIV-1复制的细胞中调节病毒基因表达和复制的协同性。神经病理和细胞培养核心将作为一个中央服务设施，用于接收、评估和分发临床样本，并为每个项目准备特定的细胞培养和病毒库存。这个 行政核心将处理与项目有关的所有行政活动，如赠款管理、采购、发货、进度报告、协议等。

Signaling pathways modulating HIV-1 induced injury in CNS The central goals and objective of this competing renewal program project remain on the utilization of a multidisciplinary approach to decipher the molecular signaling events that mediate development of brain cell injury upon HIV-1 infection. HIV-1 infection of brain microglia and perivascular macrophages as well as astrocytes leads to the secretion of viral and cellular factors causing chronic inflammation, triggering signal transduction and inducing oxidative stress. All these events can impact on the overall replication of HIV-1 in infected cells, and via a complicated chain of cytoplasmic reactions, transmit signals to the nuclei of the uninfected cells such as neurons, hence leading to gene-directed neuronal death and apoptosis. In this research program, we will employ a number of molecular, genetic, virological, and neuropathological approaches to launch a truly multidisciplinary effort for understanding signaling events that are involved in the neuropathogensis of HIV-1 infection in the brain. Thus, the central theme of this program rests on studying HIV-1-CNS interaction by focusing our attention on the interplay between viral protein such as Tat and Vpr, and host signaling pathways that control host homeostasis. In Project #1, we will aim to investigate the role of Tat in inducing neuronal cell dysfunction by focusing our attention on Rho GTPases, one of the most influential biological pathways in neuronal cell differentiation and survival. In Project #2, we will test the hypothesis that degeneration of neuronal processes is caused by TNFa-induced interaction between phosphorylated IRS-1, a key component of IGF signaling pathway, and integrins that leads to the retraction of neuronal processes. Finally, in Project #3, we will investigate the impact of HIV-1 infection on oxidative stress factors such as hypoxia inducible factor 1 (HIF-1) and the cooperativity of HIF-1 and Vpr in the regulation of viral gene expression and replication in cells supporting HIV-1 replication in the brain. The Neuropathological and Cell Culture Core will function as a central service facility for receiving, evaluating, and distributing clinical samples and preparing specific cell cultures and viral stocks to each project. The Administrative Core will handle all administrative activities related to the project such as grant management, purchasing, shipment, progress reports, protocols, etc.