STAT3 and astrogliogenesis in HIV-1 associated dementia

HIV-1 相关痴呆中的 STAT3 和星形胶质细胞生成

基本信息

  • 批准号:
    7939642
  • 负责人:
  • 金额:
    $ 18.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-28 至 2012-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Active neurogenesis occurs throughout life and relies upon the proliferation, migration and proper differentiation of neural stem/progenitor cells (NPCs). Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and activated MP inhibit neurogenesis, while enhancing astrogliogenesis in vitro and in vivo, through secretion of inflammatory cytokines such as IL-1b and TNF-a. Our preliminary study showed both IL-1b and TNF-a, as well as HIV-1-infected and LPS-activated MP induced STAT3 activation, a critical pathway of astrogliogenesis. Furthmore, microRNA-9 (miR-9) and brain-specific microRNA-124 (miR-124), factors shown to inhibit STAT3 activation, promote neuronal differentiation and inhibit astrocyte differentiation, are decreased in response to cytokine (IL-1b and TNF-a) treatment. Based on these observations, we hypothesize that HIV-1-infected and immune-activated MP promote NPC astrogliogenesis through secreted factors including cytokines (IL-1b and TNF-a) via the STAT3 pathway, and that miR-9 and miR-124 regulate this process through modulation of STAT3 activation. In this proposal, we will study the STAT3 pathway in NPCs following stimulation with inflammatory cytokines (including IL-1b and TNF-a) and HIV-1-infected and immune-activated MP and examine the effect on astrogliogenesis. We will also investigate the role of miRNAs (miR-9 and miR-124) in STAT3 activation and the modulation of human NPC differentiation mediated by cytokines (IL-1b and TNF-a) and HIV-1-infected and activated MP. We will test this hypothesis using a primary human NPC culture system and a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model. This research will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS. In addition, the work will also identify potential targets for therapeutic intervention for neural stem cell therapy. PUBLIC HEALTH RELEVANCE: Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia, in which HIV-1-infected and immune-activated macrophages drive central nervous system (CNS) inflammation. The study of the factors produced by these inflammatory cells and the signaling pathways involved in neural stem/progenitor cell differentiation will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS, and identify potential targets for therapeutic intervention for neural stem cell therapy.
描述(由申请人提供):活跃的神经发生发生在整个生命过程中,并且依赖于神经干/祖细胞(NPC)的增殖、迁移和适当分化。成人神经发生减少被认为是 HIV-1 相关痴呆 (HAD) 发病机制的潜在因素。在 HAD 中,HIV-1 感染和免疫激活的大脑单核吞噬细胞(MP;血管周围巨噬细胞和小胶质细胞)会导致中枢神经系统 (CNS) 炎症,并可能改变正常的神经发生。我们之前证明,HIV-1感染并激活的MP可抑制神经发生,同时通过分泌IL-1b和TNF-a等炎性细胞因子,在体外和体内增强星形胶质细胞生成。我们的初步研究表明 IL-1b 和 TNF-a 以及 HIV-1 感染和 LPS 激活的 MP 诱导 STAT3 激活,这是星形胶质细胞生成的关键途径。此外,microRNA-9 (miR-9) 和大脑特异性 microRNA-124 (miR-124) 是抑制 STAT3 激活、促进神经元分化和抑制星形胶质细胞分化的因子,在细胞因子(IL-1b 和 TNF-a)治疗后会减少。基于这些观察结果,我们假设 HIV-1 感染和免疫激活的 MP 通过 STAT3 途径通过包括细胞因子(IL-1b 和 TNF-a)在内的分泌因子促进 NPC 星形胶质细胞生成,并且 miR-9 和 miR-124 通过调节 STAT3 激活来调节这一过程。在本提案中,我们将研究炎症细胞因子(包括 IL-1b 和 TNF-a)以及 HIV-1 感染和免疫激活 MP 刺激后 NPC 中的 STAT3 通路,并检查其对星形胶质细胞生成的影响。我们还将研究 miRNA(miR-9 和 miR-124)在 STAT3 激活以及细胞因子(IL-1b 和 TNF-a)以及 HIV-1 感染和激活的 MP 介导的人类 NPC 分化调节中的作用。我们将使用原代人类 NPC 培养系统和严重联合免疫缺陷 (SCID) HIV-1 脑炎 (HIVE) 小鼠模型来检验这一假设。这项研究将产生重要数据,以破译大脑炎症在中枢神经系统进行性 HIV-1 感染过程中神经发生中的作用。此外,这项工作还将确定神经干细胞治疗干预的潜在靶点。 公共卫生相关性:成人神经发生减少被认为是 HIV-1 相关痴呆发病机制的潜在因素,其中 HIV-1 感染和免疫激活的巨噬细胞会导致中枢神经系统 (CNS) 炎症。对这些炎症细胞产生的因子以及参与神经干/祖细胞分化的信号通路的研究将产生重要的数据,以破译中枢神经系统进行性HIV-1感染期间脑炎症在神经发生中的作用,并确定神经干细胞治疗干预的潜在靶点。

项目成果

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Hui Peng其他文献

Hui Peng的其他文献

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{{ truncateString('Hui Peng', 18)}}的其他基金

microRNA-124 restores nerurogenesis in HIV-1 associated neurocognitve disorders
microRNA-124 恢复 HIV-1 相关神经认知障碍的神经发生
  • 批准号:
    8877662
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:
microRNA-124 restores nerurogenesis in HIV-1 associated neurocognitve disorders
microRNA-124 恢复 HIV-1 相关神经认知障碍的神经发生
  • 批准号:
    9036544
  • 财政年份:
    2014
  • 资助金额:
    $ 18.38万
  • 项目类别:

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