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：
9914883
负责人：
Eliseo A Eugenin
金额：
$ 52.54万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914883
关键词：
Anti-Retroviral Agents Apoptosis Apoptotic Area Astrocytes Autophagocytosis Biology Brain Calcium Calcium Signaling Cells Cognitive deficits Communication Connexin 43 Connexins Cytoplasm Data Dementia Development Dinoprostone Docking Ensure Exhibits Functional disorder Funding Gap Junctions Glutamates Goals HIV HIV Infections HIV-1 Human Impaired cognition In Vitro Individual Inflammatory Inositol Ions Journals Laboratories Lipids Liquid substance Maintenance Medical center Medicine Microglia Minor Mitochondria Monkeys Nervous System Physiology Nervous System Trauma Neuraxis Neuroglia Neurologic Neurologic Dysfunctions Neurons Pathogenesis Pathway interactions Peer Review Peptides Persons Play Population Prevalence Primary Infection Prostaglandins Public Health Publications RNA Research Resistance Role SIV Second Messenger Systems Signal Transduction Structure Synapses Testing Tissue Sample Tissues Toxic effect Universities Virus Replication antiretroviral therapy base brain tissue college cytochrome c gap junction channel in vivo macrophage mitochondrial dysfunction motor deficit motor impairment nervous system disorder neuroAIDS neurotoxic neurotoxicity new therapeutic target novel receptor sensitivity recruit release factor response success trafficking tripolyphosphate

项目摘要

Abstract: As of 2014, an estimated 35 million persons worldwide were living with human immunodeficiency virus (HIV). Early after primary infection, HIV enters the CNS and causes long lasting cognitive and motor impairment in 30-60 % of infected individuals, even in the current antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications has been increasing. In the CNS, HIV infects mostly microglia/macrophages, but also a small population of astrocytes. However, despite the key roles of astrocytes in CNS functions, the role of these cells in NeuroAIDS has been relatively ignored. Our studies during the last funding period provide strong evidence for the critical role of astrocytes in the pathogenesis of NeuroAIDS. In particular, we have demonstrated that despite relatively low numbers of infected astrocytes and low to undetectable HIV replication, the HIV infected astrocytes transmit apoptotic and inflammatory signals, including calcium and inositol triphosphate (IP3), to neighboring uninfected cells, promoting neuronal damage and demise. We have also shown that these pro-apoptotic molecules are spread from the few HIV infected astrocytes via connexin-43 (Cx43) containing gap junctions (GJ) and unopposed hemichannels (uHC), whose expression and opening is regulated by HIV. Indeed, blocking GJ or uHC reduced amplification of bystander apoptosis, cellular dysfunction, synaptic compromise, and mitochondrial dysfunction induced by HIV infected astrocytes. Interestingly, HIV infected astrocytes themselves are protected from apoptosis by mechanisms that involve altered apoptosome formation and mitochondrial function. Importantly, we have tested and validated most of the mechanisms operating in HIV infected astrocytes in vivo in human and monkey brain tissue sections. Thus, based on the results obtained during the extremely productive period funded by our first R01 (resulting in over 40 publications in high quality peer reviewed journals) we have formulated our current hypothesis that “HIV infected astrocytes survive HIV infection to become HIV reservoirs, and that these cells send toxic, pro-apoptotic signals to surrounding cells via Cx43 containing channels, leading to the CNS dysfunction and NeuroAIDS”. In this application we propose to characterize the novel pathways of HIV toxicity within the brain and to identify the role of GJ and uHC in CNS dysfunction. The results obtained from this proposal will lead to the identification of potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS.

抽象的：截至2014年，全球估计有3500万人患有人类免疫缺陷病毒（艾滋病病毒）。初次感染后的早期，HIV进入中枢神经系统，并引起持久的认知和运动即使在当前的抗逆转录病毒时代，也有30-60％的感染个体受损。作为感染的人寿命更长，神经系统并发症的患病率一直在增加。在中枢神经系统中，艾滋病毒感染小胶质细胞/巨噬细胞，但也有少量的星形胶质细胞。但是，dospite是钥匙星形胶质细胞在CNS功能中的作用，这些细胞在神经辅助中的作用相对忽略。我们的在上一期间的研究期间的研究为星形胶质细胞的关键作用提供了有力的证据神经辅助的发病机理。特别是，我们已经证明了欲望的数字相对较少感染的星形胶质细胞和低至无法检测的HIV复制，HIV感染的星形胶质细胞传播凋亡和炎症信号，包括钙和三磷酸钙（IP3），邻近未感染的细胞，促进神经元损害和灭亡。我们还表明，这些促凋亡分子是通过含有间隙连接（GJ）的连接蛋白43（CX43）从受HIV感染的星形胶质细胞（GJ）和无反对的半通道（UHC），其表达和开放受HIV调节。确实，阻止GJ 或UHC减少旁观者凋亡，细胞功能障碍，突触妥协和由HIV感染的星形胶质细胞诱导的线粒体功能障碍。有趣的是，艾滋病毒感染的星形胶质细胞通过涉及改变凋亡组形成和线粒体功能。重要的是，我们已经测试和验证了大多数运行的机制 HIV感染了人和猴子脑组织切片体内的星形胶质细胞。根据结果在我们的第一个R01资助的极其富有成效的时期中获得（导致40多个出版物在高质量的同行评审期刊中）我们已经提出了当前的假设，即“艾滋病毒感染星形胶质细胞生存于HIV感染成为HIV储层，并且这些细胞会发出有毒的促凋亡通过包含CX43的通道向周围细胞的信号，导致CNS功能障碍和神经辅助”。在此应用中，我们建议表征艾滋病毒毒性的新途径大脑并确定GJ和UHC在CNS功能障碍中的作用。从本提案中获得的结果将导致识别潜在的新型治疗靶标，以限制神经辅助。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of connexin/pannexin containing channels in infectious diseases.

DOI：
10.1016/j.febslet.2014.01.030
发表时间：
2014-04-17
期刊：
FEBS letters
影响因子：
3.5
作者：
Eugenin EA
通讯作者：
Eugenin EA

Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread.

DOI：
10.1038/s41598-017-16600-1
发表时间：
2017-11-30
期刊：
Scientific reports
影响因子：
4.6
作者：
Okafo G;Prevedel L;Eugenin E
通讯作者：
Eugenin E

HIV infection of astrocytes compromises inter-organelle interactions and inositol phosphate metabolism: A potential mechanism of bystander damage and viral reservoir survival.

DOI：
10.1016/j.pneurobio.2021.102157
发表时间：
2021-11
期刊：
Progress in neurobiology
影响因子：
6.7
作者：
Malik S;Valdebenito S;D'Amico D;Prideaux B;Eugenin EA
通讯作者：
Eugenin EA

Development of imaging techniques to study the pathogenesis of biosafety level 2/3 infectious agents.

开发成像技术来研究生物安全 2/3 级传染原的发病机制。

DOI：
10.1111/2049-632x.12199
发表时间：
2014
期刊：
Pathogens and disease
影响因子：
3.3
作者：
Rella,CourtneyE;Ruel,Nancy;Eugenin,EliseoA
通讯作者：
Eugenin,EliseoA

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions.

DOI：
10.1038/s41598-021-93775-8
发表时间：
2021-07-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Valdebenito S;Malik S;Luu R;Loudig O;Mitchell M;Okafo G;Bhat K;Prideaux B;Eugenin EA
通讯作者：
Eugenin EA