Signaling Pathways Modulating HIV-1 Induced Injury in CNS

调节 HIV-1 引起的中枢神经系统损伤的信号通路

• 批准号: 7686782
• 负责人: SHOHREH AMINI
• 金额: $ 115.89万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686782
• 关键词: Signaling; Pathways; Modulating; HIV; Induced

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

描述（由申请人提供）：调节CNS中HIV-1损伤的信号通路该竞争性更新计划项目的中心目标和目标仍然是使用多学科方法来破译分子信号事件，从而介导HIV-1感染时介导脑细胞损伤的发育的分子信号事件。 HIV-1脑小胶质细胞和血管周围巨噬细胞以及星形胶质细胞的感染导致病毒和细胞因子的分泌，导致慢性炎症，触发信号转导和诱导氧化应激。所有这些事件都会影响感染细胞中HIV-1的总体复制，以及通过复杂的细胞质反应链，将信号传递到未感染细胞（例如神经元）的核，因此导致基因导向神经元死亡和凋亡。在该研究计划中，我们将采用许多分子，遗传学，病毒学和神经病理学方法来启动真正的多学科工作，以理解大脑中HIV-1感染的神经性疾病涉及的信号事件。因此，该程序的中心主题在于研究HIV-1-CNS相互作用，通过将注意力集中在病毒蛋白（例如TAT和VPR）之间的相互作用以及控制宿主体内稳态的宿主信号通路之间的相互作用。在项目＃1中，我们将通过将注意力集中在Rho GTPases上来研究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，我们将检验以下假设：神经元过程的变性是由TNFA诱导的磷酸化IRS-1之间的相互作用引起的，IRS-1是IGF信号通路的关键组成部分，而整联蛋白会导致神经元过程的回缩。最后，在项目＃3中，我们将研究HIV-1感染对氧化应激因素（例如缺氧诱导因子1（HIF-1））的影响以及HIF-1和VPR的合作性