权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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，估计全世界有 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）。原发感染后不久，HIV 就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，即使在抗逆转录病毒时代也是如此。随着感染者寿命的延长，HIV 中枢神经系统感染引起的神经系统并发症的患病率有所增加。 HIV-1 引起神经发病或 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，并且检测到的病毒产量很少甚至无法检测到。尽管如此，我们的数据首次证明，HIV 感染的星形胶质细胞通过间隙连接通道甚至半通道，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 感染的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、BBB 破坏和 DKK1 分泌，导致 CNS 功能障碍，即使在当前的抗逆转录病毒时代，也经常在 HIV 感染人群中观察到，其中病毒复制极小。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，以及细胞活化和炎症的放大在HIV感染的星形胶质细胞和未感染的细胞中。这些数据将描述大脑内艾滋病毒毒性的新途径，并将确定这些通道在中枢神经系统功能障碍中的作用。从该提案中获得的结果应该表明潜在的新治疗靶点，以限制神经艾滋病的破坏性后果。 PHS 398/2590（修订版 06/09）页面延续格式页面公共卫生相关性：随着抗逆转录病毒疗法的成功，艾滋病毒感染者的寿命越来越长，这些感染人群中认知和运动缺陷的患病率正在增加。星形胶质细胞在维持中枢神经系统功能中发挥着关键作用。然而，它们在 NeuroAIDS 发病机制中的作用尚未得到很好的表征，主要是由于缺乏检查星形胶质细胞的 HIV 感染的特定分子工具。体内和体外检查星形胶质细胞的 HIV 感染及其在大脑中的后果的新技术的发展使我们能够证明星形胶质细胞中的间隙连接（GJ）和半通道（uHC）在 NeuroAIDS 的发病机制中很重要。我们的研究已经表明，尽管 HIV 感染细胞数量很少且病毒复制也很少，但 Connexin43 (Cx43) 的 GJ 和 uHC 对于向邻近细胞扩散损伤至关重要。我们建议扩大这些研究，以表征未感染的星形胶质细胞、神经元和脑内皮细胞的旁观者失调。此外，我们将通过检查 GJ 和 uHC 的激活和调节来研究 GJ 和 uHC 向邻近细胞传递和放大毒性信号的分子机制。最后，我们将通过使用一种新的旁观者毒性动物模型来扩展我们在体内获得的初步数据，该模型是通过将少量人类HIV感染的人类星形胶质细胞显微注射到Cx43基因删除的星形胶质细胞的动物大脑中介导的。我们将使用这些动物来评估显微注射的 HIV 感染星形胶质细胞周围邻近细胞的细胞凋亡和 BBB 破坏。这些研究的结果可能为开发治疗艾滋病毒感染者神经功能障碍的疗法提供信息。