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3300万人生活在人类免疫缺陷病毒（HIV）感染（单词健康组织和联合国估计）中。初次感染后的早期，HIV进入中枢神经系统，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。随着感染个体的寿命更长，由于艾滋病毒感染引起的神经系统并发症的流行率增加了。 HIV-1引起神经病发生或神经辅助的细胞基础和机制仍未得到充分了解。星形胶质细胞是CNS中调节BBB完整性，CNS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，并检测到低病毒的产生。然而，我们的数据首次证明了艾滋病毒感染的星形胶质细胞通过间隙连接通道和半通道可以扩增炎症和中枢神经系统损伤。 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病毒复制很小。为了解决这一假设，我们将扩展我们的广泛初步研究，证明这些通道参与神经元，星形胶质细胞和血液脑屏障（BBB）功能障碍，以及在HIV感染的细胞激活和炎症中的扩增，以及在未感染的细胞中。这些数据将表征大脑内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。从该提案中获得的结果应表明潜在的新型治疗靶标，以限制神经辅助的破坏性后果。