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: 8329102
• 负责人: Eliseo A Eugenin
• 金额: $ 37.53万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ 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/8329102
• 关键词: AIDS neuropathy; Address; Animal Model; Animals; Anti-Retroviral Agents; Apoptosis; Area; Astrocytes; Blood - brain barrier anatomy; Brain; Cell Death; Cell surface; Cells; Central Nervous System Infections; Characteristics; Cognitive deficits; Collaborations; Communication; Connexin 43; Cytoplasm; Data; Dementia; Development; Endothelial Cells; Extracellular Space; Functional disorder; Gap Junctions; Goals; HIV; HIV-1; Homologous Gene; Human; Immune; Immune response; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Investigation; Knockout Mice; Letters; Life; Mediating; Microglia; Microinjections; Minor; Molecular; Mus; Nervous System Physiology; Nervous System Trauma; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Neuropathogenesis; Pathogenesis; Pathway interactions; Persons; Play; Population; Prevalence; Principal Investigator; Production; Proteins; Public Health; Publications; Regulation; Research; Role; Signal Transduction; Techniques; Time; Toxic effect; Universities; Viral; Virus Diseases; antiretroviral therapy; base; gap junction channel; health organization; in vivo; inhibitor/antagonist; macrophage; migration; motor deficit; motor impairment; mouse model; nervous system disorder; neuronal survival; new therapeutic target; novel; programs; research study; success; therapy development; tool

DESCRIPTION (provided by applicant): As of 2010, an estimated 34 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 minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the 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 astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: As individuals with HIV are living longer due to the success of antiretroviral therapies, the prevalence of cognitive and motor deficits in this infected populatio is increasing. Astrocytes play a key role in maintaining CNS functions. However, their role in the pathogenesis of NeuroAIDS has not been well characterized, mainly due to the lack of specific molecular tools to examine HIV infection of astrocytes. The development of novel techniques to examine HIV infection of astrocytes in vivo and in vitro and their consequences in brain enable us to demonstrate that gap junction (GJ) and hemichannels (uHC) in astrocytes are important in the pathogenesis of NeuroAIDS. Our studies already showed that GJ and uHC of Connexin43 (Cx43) are critical to spread damage to neighboring cells despite the few numbers of HIV infected cells and minimal viral replication. We propose to expand these studies to characterize bystander dysregulation of uninfected astrocytes, neurons and brain endothelial cells. In addition, we will study the molecular mechanism by which GJ and uHC transmit and amplify toxic signals to neighboring cells by examining their activation and regulation. Lastly, we will expand upon our preliminary data obtained in vivo by using a novel animal model of bystander toxicity mediated by microinjection of few human HIV infected human astrocytes into the brain of animals with astrocytes genetically deleted for Cx43. We will evaluate using these animals, apoptosis and BBB disruption in neighboring cells around the microinjected HIV infected astrocytes. The results of these studies may provide information for the development of therapies to treat the neurologic dysfunctions in HIV infected individuals.

描述（由申请人提供）：截至2010年，全球估计有3400万人感染人类免疫缺陷病毒（HIV）（世界卫生组织和联合国估计）。在初次感染后的早期，即使在抗逆转录病毒时代，艾滋病毒也会进入中枢神经系统，导致30-60%的感染者出现认知和运动障碍。随着感染者寿命的延长，由HIV中枢神经系统感染引起的神经系统并发症的发生率也在增加。HIV-1引起神经发病或神经艾滋病的细胞基础和机制尚不清楚。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。艾滋病毒仅感染这些细胞中的一小部分，并且检测到的病毒产量很少，甚至无法检测到。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可能的半通道，可以放大炎症和中枢神经系统损伤。我们假设含有间隙连接（GJ）和半通道（uHC）的Cx43将少数HIV感染星形胶质细胞中产生的细胞间信号放大到周围未感染的细胞，从而导致细胞毒性、血脑屏障破坏和DKK1的分泌，导致即使在当前抗逆转录病毒时代病毒复制最小的HIV感染人群中也经常观察到的中枢神经系统功能障碍。为了解决这一假设，我们将扩展我们广泛的初步研究，证明这些通道参与星形胶质细胞，神经元和血脑屏障（BBB）功能障碍，以及细胞激活和炎症的放大