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: 8300958
• 负责人: Lena Al-Harthi
• 金额: $ 35.99万
• 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 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300958
• 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; 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

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/¿-catenin activity is a pro-survival signal in neurons and astrocytes. Wnt/¿-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 ¿-catenin and neurodegeneration. Yet, the role of Wnt/¿-catenin activity in NeuroAIDS is unclear. We reported an inverse relationship between Wnt/¿-catenin activity and HIV replication. Specifically, we demonstrated that active Wnt/¿-catenin inhibits whereas inactive Wnt/¿-catenin induces HIV replication. Further, IFN¿, a proinflammatory cytokine associated with HAD severity, and Tat, an HIV-encoded regulatory protein, both diminished Wnt/¿-catenin signaling in astrocytes. We propose that (i) Wnt/¿-catenin signaling (Wnt) is a key regulator of HIV replication and homeostasis in the brain, and (ii) Wnt down-regulation (mediated by Tat or IFN¿) 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/¿-catenin expression) we will define the mechanism by which Wnt/¿-catenin regulates HIV replication. In Aim 2, using astrocytes, microglia, and monocyte-derived macrophages, we will determine the role of host (IFN¿) and viral (Tat) factors in modulating Wnt/¿-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/¿-catenin activity on HIV replication and glial/neuronal survival. These studies could also expedite the development of activators of ¿-catenin signaling that can penetrate the CNS, suppress HIV replication, and enhance survival of astrocytes and neurons.

艾滋病毒引起神经系统疾病（NeuroAIDS），从轻微的认知和运动障碍到艾滋病毒- 相关性痴呆（HAD）需要更好地了解NeuroAIDS的潜在机制 因为它会为神经艾滋病提出治疗方法。为了实现这一目标，我们的战略是确定 内源性神经保护机制与脑细胞中的HIV之间的相互作用。Wnt/β-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/<$-catenin调节涉及不同细胞的约500个基因 功能，如细胞增殖和生存在整个身体，包括中枢神经系统。越来越多的证据 链接降低了连环蛋白和神经变性的水平。然而，Wnt/β-连环蛋白活性在 神经艾滋病不清楚。我们报道了Wnt/β-catenin活性与HIV复制之间的反比关系。 具体来说，我们证明了活性Wnt/<$-catenin抑制HIV，而非活性Wnt/<$-catenin诱导HIV。 复制的此外，与HAD严重程度相关的促炎细胞因子IFN和HIV编码的达特， 调节蛋白，两者都减少了星形胶质细胞中的Wnt/β-连环蛋白信号传导。我们建议（i）Wnt/<$-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介导）促进星形胶质细胞和神经元凋亡，这有助于发病机制 中枢神经系统中的艾滋病。在目标1中，使用星形胶质细胞（具有高内源性Wnt/β-连环蛋白表达） 我们将确定Wnt/β-连环蛋白调节HIV复制的机制。在Aim 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）和病毒（达特）因子的作用 在调节Wnt/β-catenin信号传导和HIV复制方面。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的存活。总的来说，这些研究将使人们更好地了解 脑Wnt/ω-连环蛋白活性对HIV复制和神经胶质/神经元存活的影响。这些研究还可以加快 开发能够穿透CNS、抑制HIV复制的连环蛋白信号激活剂， 增强星形胶质细胞和神经元的存活。