Dysregualtion of gliotransmission in models of neuroHIV

神经艾滋病毒模型中神经胶质细胞传递失调

基本信息

批准号：
9135858
负责人：
Norman J Haughey
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-10 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135858
关键词：
AIDS Dementia Complex Area Astrocytes Bioinformatics Biological Biological Neural Networks Biology Cells Central Nervous System Infections Cognitive deficits Communication Complex Data Databases Dendritic Spines Development Dose Environment Functional disorder Glutamates Goals Growth HIV HIV Envelope Protein gp120 HIV Infections HIV-associated neurocognitive disorder Impaired cognition Impairment Incidence Individual Infection Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Investigation Learning Lipids Longevity Mediator of activation protein Memory MicroRNAs Minor Modeling Modification Molecular Mus Nerve Degeneration Nervous System Trauma Neural Pathways Neurites Neurobiology Neurocognitive Deficit Neuroglia Neuronal Dysfunction Neuronal Plasticity Neurons Pathway interactions Patients Prevalence Property Proteins Regulation Reporting Research Risk Rodent Model Role Severities Signal Pathway Signal Transduction Stimulus Stress Structure Synapses Systems Biology TNF gene Therapeutic Intervention Transgenic Model Vertebral column Vesicle Work antiretroviral therapy base brain volume chemokine cohort cytokine executive function exosome extracellular vesicles genome sequencing in vivo macrophage microvesicles nanovesicle neural circuit neurocognitive disorder neurotransmission neurotropic novel public health relevance relating to nervous system release factor repaired research study response synaptic function synaptogenesis transcriptome whole genome

项目摘要

DESCRIPTION (provided by applicant): Bi-directional communication between astrocytes and neurons regulates synaptic formation, synaptic strength, and participates in the regulation of neural circuitry by coordinating activity among groups of neurons. Astrocyte dysfunction in the settings of HIV-infection, and other neurodegenerative conditions has been postulated to disrupt the activity of neural networks involved in memory and executive functions. Although HIV-associated perturbations in the composition and quantity of various cytokine, chemokine and growth factors released from astrocytes have been demonstrated, these observations have thus far been insufficient to explain how astrocyte stress contributes to neuronal dysfunction. These questions are particularly important in the era of Antiretroviral Therapy (ART), where reductions in neuronal connectivity, synaptic simplification and reductions in dendritic complexity are thought to be primary contributors to cognitive impairments in HIV- infected individuals. Advancements in our understanding of the biology of extracellular vesicles have begun to implicate glial released microvesicles as primary mediators of glia to neuron communication. In preliminary experiments we provide evidence that a variety of stimuli can induce astrocytes to shed microvesicles. The molecular cargo of astrocyte-shed microvesicles was complex and contained more than 200 distinct proteins, 100 miRNA, and hundreds of bioreactive lipid species. Moreover, the protein, miRNA and lipid composition of astrocyte exosomes was modified by the stimulus used to induce release. These astrocyte-shed exosomes directly interacted with neurons to modify neuronal structure and function. Based on these preliminary findings we reasoned that a scientific focus on any one protein, lipid or miRNA would be unlikely to produce a true representation of the functions regulated by this complex signaling vesicles. Therefore, we used bioinformatic and systems biology approaches to understand how the protein, miRNA and lipid composition of exosomes interacts to regulate neuronal signaling pathways identified by whole genome sequencing of target neurons. In this application we focused our efforts on a small number of the identified pathways. In particular we concentrated on neural pathways associated with synapse formation, spine formation, and neurite outgrowth, as these neuronal structures appear to be damaged in many HIV infected individuals. The goals of this application are to understand how endogenous excitatory stimuli and inflammatory stimuli associated with HIV-infection modulate the cargo of astrocyte-shed exosomes and how these exosomes regulate/dysregulate the structure and function of their target neurons.

描述（由申请人提供）：星形胶质细胞和神经元之间的双向通信调节突触形成、突触强度，并通过协调 HIV 感染和其他情况下星形胶质细胞功能障碍来参与神经回路的调节。神经退行性疾病被认为会破坏参与记忆和执行功能的神经网络的活动，尽管艾滋病毒相关的各种细胞因子、趋化因子和生长因子的成分和数量受到干扰。星形胶质细胞已被证明，但迄今为止这些观察结果不足以解释星形胶质细胞应激如何导致神经元功能障碍，这些问题在抗逆转录病毒治疗（ART）时代尤为重要，因为在抗逆转录病毒治疗中，神经元连接性减少，突触简化和树突复杂性降低。被认为是 HIV 感染者认知障碍的主要原因。我们对细胞外囊泡生物学认识的进步已经开始表明神经胶质细胞的释放。在初步实验中，我们提供的证据表明，多种刺激可以诱导星形胶质细胞脱落微泡，星形胶质细胞脱落的微泡的分子货物很复杂，包含 200 多种不同的蛋白质、100 种 miRNA 和 100 多种不同的蛋白质。此外，星形胶质细胞外泌体的蛋白质、miRNA 和脂质成分被用于诱导这些星形胶质细胞脱落的刺激物所改变。外泌体直接与神经元相互作用以改变神经元的结构和功能，基于这些初步发现，我们推断，对任何一种蛋白质、脂质或 miRNA 的科学关注都不太可能产生这种复杂信号小泡调节的功能的真实表现。，我们使用生物信息学和系统生物学方法来了解外泌体的蛋白质、miRNA 和脂质成分如何相互作用来调节通过目标神经元的全基因组测序确定的神经元信号通路。我们特别关注与突触形成、脊柱形成和神经突生长相关的神经通路，因为这些神经结构在许多艾滋病毒感染者中似乎受到损害，该应用的目标是了解内源性兴奋性刺激和炎症刺激是如何发生的。与艾滋病毒感染相关的星形胶质细胞脱落的外泌体的货物以及这些外泌体如何调节/失调其目标神经元的结构和功能。