Signaling Pathways Modulating HIV-1 Induced Injury in CNS

描述（由申请人提供）：调节HIV-1诱导的CNS损伤的信号通路该竞争性更新计划项目的中心目标和目的仍然是利用多学科方法来破译介导HIV-1感染后脑细胞损伤发展的分子信号事件。脑小胶质细胞和血管周围巨噬细胞以及星形胶质细胞的HIV-1感染导致病毒和细胞因子的分泌，引起慢性炎症，触发信号转导并诱导氧化应激。所有这些事件都可以影响HIV-1在感染细胞中的整体复制，并通过复杂的细胞质反应链将信号传递到未感染细胞（如神经元）的细胞核，从而导致基因指导的神经元死亡和凋亡。在这项研究计划中，我们将采用一些分子，遗传学，病毒学和神经病理学的方法来启动一个真正的多学科的努力，了解参与大脑中HIV-1感染的神经发病机制的信号事件。因此，该项目的中心主题在于通过将我们的注意力集中在病毒蛋白（如达特和Vpr）与控制宿主稳态的宿主信号通路之间的相互作用来研究HIV-1-CNS相互作用。在项目#1中，我们将致力于研究达特在诱导神经元细胞功能障碍中的作用，将我们的注意力集中在Rho GTP酶上，Rho GTP酶是神经元细胞分化和存活中最有影响力的生物学途径之一。在项目#2中，我们将检验以下假设：神经元过程的变性是由TNF α诱导的磷酸化IRS-1（IGF信号通路的关键组分）与整联蛋白之间的相互作用引起的，该相互作用导致神经元过程的收缩。最后，在项目#3中，我们将研究HIV-1感染对氧化应激因子如缺氧诱导因子1（HIF-1）的影响，以及HIF-1和Vpr在HIV-1感染中的协同作用。

DESCRIPTION (provided by applicant): 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