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（通过应用程序证明）：星形胶质细胞和神经元之间的双向通信调节突触形成，并通过在神经元组中巩固神经电路来调节神经回路，并参与神经元素之间的其他成本。 V.与星形胶质细胞释放的趋化因子和各种细胞因子的扰动，到目前为止，这些观察结果不足被认为是艾滋病毒感染的个体的认知障碍的原因。 Shed Microvesicle是复杂的，超过200个不同的蛋白质，由用于诱导这些星形胶质细胞释放的刺激来改变星形胶质细胞外泌体的蛋白质和脂质组成任何一种蛋白质，miRNA都会对由这种复杂信号蛋白ICLES调节的功能产生真正的共同评估。神经元，尤其是识别的途径，我们集中于与突触形成相关的神经途径，而神经突出的途径是了解内og的目标目标神经元的结构功能。