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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.

摘要：截至2014年，全世界估计有3 500万人感染人类免疫缺陷病毒（艾滋病毒）。在初次感染后早期，HIV进入CNS并引起长期的认知和运动障碍。即使在当前的抗逆转录病毒时代，30- 60%的感染者也会出现损伤。作为感染者随着寿命的延长，神经系统并发症的患病率也在增加。在中枢神经系统，艾滋病毒主要感染小胶质细胞/巨噬细胞，但也感染小群体的星形胶质细胞。然而，尽管关键虽然星形胶质细胞在CNS功能中的作用，但这些细胞在NeuroAIDS中的作用相对被忽视。我们在上一个资助期的研究提供了强有力的证据，星形胶质细胞在神经艾滋病的发病机制。特别是，我们已经证明，尽管相对较低的数量，感染的星形胶质细胞和低至检测不到的HIV复制，HIV感染的星形胶质细胞将凋亡的和炎症信号，包括钙和肌醇三磷酸（IP 3），邻近未感染的细胞，促进神经元损伤和死亡。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）从少数HIV感染的星形胶质细胞传播，非对抗半通道（uHC），其表达和开放受HIV调节。事实上，阻止GJ 或uHC减少旁观者细胞凋亡、细胞功能障碍、突触损害的放大，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它们自身通过涉及改变的线粒体形成的机制而免受凋亡，线粒体功能重要的是，我们已经测试和验证了大多数机制的运作，人类和猴子脑组织切片中体内HIV感染的星形胶质细胞。因此，根据结果，在我们的第一个R 01资助的极其富有成效的时期获得的（导致40多个出版物在高质量的同行评审期刊上），我们已经制定了我们目前的假设，即“艾滋病毒感染者” 星形胶质细胞在HIV感染后存活下来，成为HIV的储存库，这些细胞发出有毒的、促凋亡的信号，通过含有Cx43的通道向周围细胞发出信号，导致CNS功能障碍，神经艾滋病”。在本申请中，我们提出表征HIV毒性的新途径，脑中，并确定GJ和uHC在CNS功能障碍中的作用。从这一建议中获得的结果将导致识别潜在的新的治疗靶点，以限制神经艾滋病

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）

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

Role of connexin/pannexin containing channels in infectious diseases.

连接性疾病中含有通道的连接蛋白/泛毒素的作用。

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

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