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：
8467056
负责人：
Eliseo A Eugenin
金额：
$ 13.98万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467056
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

描述（由申请人提供）：截至2010年，全球估计有3400万人患有人类免疫缺陷病毒（HIV）感染（单词健康组织和联合国估计）。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仅感染了这些细胞中的一小部分，并且检测到无法检测到的病毒产生最少。然而，我们的数据首次证明了HIV感染的星形胶质细胞通过间隙连接通道以及可能的半通道可以扩大炎症和CNS损伤。我们假设CX43含有间隙连接（GJ）和半通道（UHC）（UHC）扩增了在几个HIV感染的HIV感染的星形胶质细胞中产生的细胞间信号，从而导致细胞毒性，BBB毒性，BBB扰动和分泌DKK1通常会导致CNS的凝聚力，从而导致CNS的凝聚力均具有HIV的范围，从而在HIV中受到了感染的范围，而HIV的群体受到了感染的范围。病毒复制很小。为了解决这个假设在HIV感染的星形胶质细胞和未感染的细胞中。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CNS功能障碍中的作用。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。 PHS 398/2590（修订版06/09）页面延续格式页面