Interplay between neuroprotective pathways, HIV, and astrocytes

神经保护途径、HIV 和星形胶质细胞之间的相互作用

• 批准号: 8112015
• 负责人: Lena Al-Harthi
• 金额: $ 36.32万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112015
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Address; Anti-HIV Agents; Apoptosis; Apoptotic; Astrocytes; Binding; Binding Sites; Brain; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Cognition Disorders; Cognitive; Data; Development; Disease; Down-Regulation; Event; Genes; Genetic Transcription; Glycogen Synthase Kinases; Goals; HIV; HIV Infections; Health; Homeostasis; Human; Impairment; Individual; Invaded; Kinetics; Lead; Link; Mediating; Microglia; Minor; Modeling; Nerve Degeneration; Neuraxis; Neurologic; Neurons; Neuropathogenesis; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Predisposition; Property; Regulation; Reporting; Repression; Resistance; Role; Severities; Signal Transduction; Site; Stream; System; TCF7L2 gene; TNF gene; Therapeutic; Transcription Initiation; Viral; Viral Proteins; Viral Regulatory Proteins; base; brain cell; combat; cytokine; fetal; gene repression; genetic regulatory protein; macrophage; monocyte; motor disorder; nervous system disorder; neuron apoptosis; neuronal survival; novel

DESCRIPTION (provided by applicant): HIV causes neurologic disorders (NeuroAIDS) ranging from minor cognitive and motor disorders to HIV- associated dementia (HAD). A better understanding of the underlying mechanisms of NeuroAIDS is needed because it would suggest therapeutic approaches for NeuroAIDS. Towards this goal, our strategy is to define the interplay between endogenous neuroprotective mechanisms and HIV in brain cells. Wnt/2-catenin activity is a pro-survival signal in neurons and astrocytes. Wnt/2-catenin regulates ~500 genes involved in diverse cell functions such as cell proliferation and survival throughout the body, including the CNS. Mounting evidence links decreased levels of 2-catenin and neurodegeneration. Yet, the role of Wnt/2-catenin activity in NeuroAIDS is unclear. We reported an inverse relationship between Wnt/2-catenin activity and HIV replication. Specifically, we demonstrated that active Wnt/2-catenin inhibits whereas inactive Wnt/2-catenin induces HIV replication. Further, IFN3, a proinflammatory cytokine associated with HAD severity, and Tat, an HIV-encoded regulatory protein, both diminished Wnt/2-catenin signaling in astrocytes. We propose that (i) Wnt/2-catenin signaling (Wnt) is a key regulator of HIV replication and homeostasis in the brain, and (ii) Wnt down-regulation (mediated by Tat or IFN3) promotes astrocyte and neuronal apoptosis, which contributes to the pathogenesis of HIV disease in the CNS. In Aim 1, using astrocytes (which have high endogenous Wnt/2-catenin expression) we will define the mechanism by which Wnt/2-catenin regulates HIV replication. In Aim 2, using astrocytes, microglia, and monocyte-derived macrophages, we will determine the role of host (IFN3) and viral (Tat) factors in modulating Wnt/2-catenin signaling and HIV replication. In Aim 3, using primary human fetal mixed glial/neuronal brain cell cultures, we will determine the consequences of modulation of brain Wnt activity on the survival of astrocytes and neurons. Collectively, these studies will lead to a better understanding of the role of brain Wnt/2-catenin activity on HIV replication and glial/neuronal survival. These studies could also expedite the development of activators of 2-catenin signaling that can penetrate the CNS, suppress HIV replication, and enhance survival of astrocytes and neurons. PUBLIC HEALTH RELEVANCE: Despite anti-HIV drug therapy, approximately 50% of HIV-infected individuals develop cognitive and motor disorder. This may be due to the poor permeability of current anti-HIV drugs into the brain. Because neurons are not directly infected by HIV, their death/dysregulation is thought to occur through indirect events. Our application will examine the interplay between a pathway that is defined as neuroprotective (Wnt/2-catenin), HIV replication in brain cells, and role of astrocytes in mediating HIV-associated neuropathogenesis. We have established that the Wnt/2-catenin pathway inhibits HIV replication. When this pathway is on, HIV level is low and when it is off, HIV level is high. We demonstrated this relationship in astrocytes, which express high level of Wnt/2-catenin. When astrocytes were first treated with IFN3 then infected, HIV levels were higher. This then suggests that signals that turn off this pathway, such as IFN3, will allow for burst of low-level of HIV. This will then lead to increased Tat level (a viral protein that is linked to apoptosis of astrocytes and neurons). Tat, we demonstrated, in turn turns off the Wnt/2-catenin pathway, leading to higher level of HIV replication in HIV target cells. The consequence of these events is diminished Wnt/2-catenin activity in the brain, which will lead to increased susceptibility of astrocytes and neurons to cell death. This model places the Wnt/2-catenin pathway at the interface of HIV-mediated neuropathogenesis through both direct (active HIV replication) and indirect (enhanced cell death) events. Clarifying this interplay could lead to novel drug strategies to combat HIV infection in the brain.

描述（由申请人提供）：HIV引起神经系统疾病（NeuroAIDS），范围从轻微的认知和运动障碍到HIV相关性痴呆（HAD）。需要更好地了解NeuroAIDS的潜在机制，因为它将为NeuroAIDS提供治疗方法。为了实现这一目标，我们的策略是确定内源性神经保护机制和脑细胞中的HIV之间的相互作用。Wnt/2-连环蛋白活性是神经元和星形胶质细胞中的促存活信号。Wnt/2-catenin调节约500个基因，这些基因参与不同的细胞功能，如细胞增殖和整个身体（包括CNS）的存活。越来越多的证据将2-连环蛋白水平的降低与神经退行性变联系起来。然而，Wnt/2-catenin活性在NeuroAIDS中的作用尚不清楚。我们报道了Wnt/2-catenin活性和HIV复制之间的反比关系。具体来说，我们证明了活性Wnt/2-catenin抑制，而非活性Wnt/2-catenin诱导HIV复制。此外，IFN 3，一种与HAD严重程度相关的促炎细胞因子，和达特，一种HIV编码的调节蛋白，都减少了星形胶质细胞中的Wnt/2-连环蛋白信号传导。我们提出（i）Wnt/2-catenin信号传导（Wnt）是脑中HIV复制和稳态的关键调节因子，和（ii）Wnt下调（由达特或IFN 3介导）促进星形胶质细胞和神经元凋亡，这有助于CNS中HIV疾病的发病机制。在目标1中，使用星形胶质细胞（具有高内源性Wnt/2-连环蛋白表达），我们将定义Wnt/2-连环蛋白调节HIV复制的机制。在目标2中，使用星形胶质细胞、小胶质细胞和单核细胞衍生的巨噬细胞，我们将确定宿主（IFN 3）和病毒（达特）因子在调节Wnt/2-连环蛋白信号传导和HIV复制中的作用。在目标3中，使用原代人胎儿混合神经胶质/神经元脑细胞培养物，我们将确定脑Wnt活性的调节对星形胶质细胞和神经元存活的影响。总的来说，这些研究将导致更好地了解大脑Wnt/2-catenin活性对HIV复制和神经胶质/神经元存活的作用。这些研究还可以加速2-连环蛋白信号传导激活剂的开发，这些激活剂可以穿透中枢神经系统、抑制艾滋病毒复制并增强星形胶质细胞和神经元的存活。公共卫生相关性：尽管有抗HIV药物治疗，但约50%的HIV感染者仍会出现认知和运动障碍。这可能是由于目前抗HIV药物对大脑的渗透性较差。由于神经元不直接被HIV感染，它们的死亡/失调被认为是通过间接事件发生的。我们的应用程序将检查被定义为神经保护（Wnt/2-catenin），HIV在脑细胞中的复制，以及星形胶质细胞在介导HIV相关神经发病机制中的作用之间的相互作用。我们已经确定Wnt/2-catenin途径抑制HIV复制。当这条途径开启时，HIV水平较低，当它关闭时，HIV水平较高。我们在表达高水平Wnt/2-catenin的星形胶质细胞中证明了这种关系。当星形胶质细胞首先用IFN 3处理然后感染时，HIV水平更高。这表明，关闭这一途径的信号，如IFN 3，将允许低水平的HIV爆发。这将导致增加的达特水平（一种与星形胶质细胞和神经元凋亡有关的病毒蛋白）。我们证明，达特反过来又关闭了Wnt/2-连环蛋白途径，导致HIV靶细胞中更高水平的HIV复制。这些事件的结果是大脑中Wnt/2-连环蛋白活性降低，这将导致星形胶质细胞和神经元对细胞死亡的易感性增加。该模型将Wnt/2-catenin途径置于HIV介导的神经发病机制的界面，通过直接（活跃的HIV复制）和间接（增强的细胞死亡）事件。澄清这种相互作用可能会导致新的药物策略来对抗大脑中的艾滋病毒感染。