Signaling Pathways Modulating HIV-1 Induced Injury in CNS

描述（由申请人提供）：调节HIV-1诱导的中枢神经系统损伤的信号通路这个竞争性更新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通路。HIV-1感染脑小胶质细胞和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，从而导致基因导向的神经元死亡和凋亡。在这个研究项目中，我们将采用一些分子、遗传、病毒学和神经病理学的方法来启动一个真正的多学科努力，以了解在大脑中HIV-1感染的神经发病机制中涉及的信号事件。因此，该计划的中心主题在于研究HIV-1-CNS相互作用，将我们的注意力集中在病毒蛋白（如Tat和Vpr）与控制宿主稳态的宿主信号通路之间的相互作用上。在Project #1中，我们将通过关注Rho GTPases来研究Tat在诱导神经元细胞功能障碍中的作用，Rho GTPases是神经元细胞分化和存活中最具影响力的生物学途径之一。在项目#2中，我们将验证一个假设，即神经元过程的退化是由tnf诱导的磷酸化IRS-1 （IGF信号通路的关键组成部分）与整合素之间的相互作用引起的，整合素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