Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍

• 批准号: 8793824
• 负责人: Eliseo A Eugenin
• 金额: $ 22.36万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793824
• 关键词: Astrocyte; connexin43; containing; channels; amplify

DESCRIPTION (provided by applicant): As of 2007, an estimated 33 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60 % of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms, by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and low viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and hemichannels, can amplify inflammation and CNS damage. Our proposal hypothesizes that Cx43 containing GJ and hemichannels amplify intracellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, astrocyte proliferation, BBB disruption and secretion of DKK1 leading to the enhanced CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in neuronal, astrocyte and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes as well as in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels during the viral life cycle in astrocytes. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS.

描述（由申请人提供）：截至2007年，全球估计有3300万人感染人类免疫缺陷病毒（HIV）（世界卫生组织和联合国估计）。在初次感染后早期，HIV进入CNS并在30- 60%的感染个体中引起认知和运动障碍，即使在抗逆转录病毒时代也是如此。随着感染者的寿命延长，HIV CNS感染引起的神经系统并发症的患病率也增加了。HIV-1引起神经发病机制或NeuroAIDS的细胞基础和机制仍不清楚。星形胶质细胞是中枢神经系统中调节血脑屏障完整性、中枢神经系统炎症、免疫反应和神经元存活的关键细胞。HIV仅感染这些细胞中的一小部分，并且检测到低病毒产量。然而，我们的数据首次表明，HIV感染的星形胶质细胞，通过间隙连接通道和半通道，可以放大炎症和CNS损伤。我们的提议假设，含有GJ和半通道的Cx43将在少数HIV感染的星形胶质细胞中产生的细胞内信号放大到周围未感染的细胞，导致细胞毒性、星形胶质细胞增殖、BBB破坏和DKK 1分泌，导致即使在病毒复制最小的当前抗逆转录病毒时代，在HIV感染人群中也经常观察到增强的CNS功能障碍。为了解决这一假设，我们将扩大我们广泛的初步研究，证明这些通道参与神经元，星形胶质细胞和血脑屏障（BBB）功能障碍，以及在HIV感染的星形胶质细胞以及未感染的细胞中细胞活化和炎症的放大。这些数据将表征脑内HIV毒性的新途径，并将确定这些通道在星形胶质细胞中病毒生命周期中的作用。从这个提议中获得的结果应该表明潜在的新的治疗靶点，以限制NeuroAIDS的破坏性后果。