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:
  • 金额:
    $ 40.5万
  • 依托单位:
  • 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

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(应用程序提供):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,并通过神经元组之间的协调活性参与神经元电路的调节。在HIV感染设置和其他神经退行性条件下,星形胶质细胞功能障碍已被假定,以破坏记忆和执行功能所涉及的神经元的活性。尽管已经证明了各种细胞因子的组成和数量中与HIV相关的扰动,但已经证明了星形胶质细胞释放的趋化因子和生长因子,但到目前为止,这些观察结果不足以解释星形胶质细胞应激如何对神经元功能障碍有效。在抗逆转录病毒疗法(ART)的时代,这些问题尤为重要,在抗逆转录病毒疗法(ART)中,神经元连通性,突触简化和树突复杂性降低的降低被认为是艾滋病毒感染者认知障碍的主要因素。我们对细胞外蔬菜生物学的理解的进步已经开始将神经胶质释放为神经元的主要介体与神经元的交流。在初步实验中,我们提供了证据,表明各种刺激可以诱导星形胶质细胞。星形胶质细胞分离微泡的分子货物很复杂,包含200多种不同的蛋白质,100 miRNA和数百种生物反应性脂质物种。此外,星形胶质细胞外泌体的蛋白质,miRNA和脂质组成是通过用于诱导释放的刺激来改变的。这些星形胶质细胞 - 外泌体直接与神经元相互作用,以修饰神经元结构和功能。基于这些初步发现,我们认为对任何一种蛋白质,脂质或miRNA的科学关注不太可能产生由这种复杂信号蔬菜调节的功能的真实表示。因此,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和脂质组成如何相互作用以调节靶神经元的整个基因组测序鉴定的神经元信号通路。在此应用程序中,我们将精力集中在少数已确定的途径上。特别是,我们集中于与突触形成,脊柱形成和神经落生相关的神经元途径,因为这些神经元结构在许多受HIV感染的个体中似乎受到损害。该应用的目标是了解与HIV感染相关的内源性兴奋性刺激和炎症性刺激如何调节星形胶质细胞 - 外泌体的货物以及这些外泌体如何调节/失调其靶神经元的结构和功能。

项目成果

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Norman J Haughey其他文献

Norman J Haughey的其他文献

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{{ truncateString('Norman J Haughey', 18)}}的其他基金

A Sphingomyelin Hydrolase Regulates the Late Stages of HIV Assembly and Budding
鞘磷脂水解酶调节 HIV 组装和出芽的后期阶段
  • 批准号:
    10548445
  • 财政年份:
    2022
  • 资助金额:
    $ 40.5万
  • 项目类别:
A Sphingomyelin Hydrolase Regulates the Late Stages of HIV Assembly and Budding
鞘磷脂水解酶调节 HIV 组装和出芽的后期阶段
  • 批准号:
    10665753
  • 财政年份:
    2022
  • 资助金额:
    $ 40.5万
  • 项目类别:
NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
NLRP 炎性体定向激活先天免疫系统,在 EcoHIV 感染小鼠自我施用芬太尼时产生突触损伤
  • 批准号:
    10085923
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:
NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
NLRP 炎性体定向激活先天免疫系统,在 EcoHIV 感染小鼠自我施用芬太尼时产生突触损伤
  • 批准号:
    10402833
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:
NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
NLRP 炎性体定向激活先天免疫系统,在 EcoHIV 感染小鼠自我施用芬太尼时产生突触损伤
  • 批准号:
    10202547
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:
NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
NLRP 炎性体定向激活先天免疫系统,在 EcoHIV 感染小鼠自我施用芬太尼时产生突触损伤
  • 批准号:
    10612471
  • 财政年份:
    2020
  • 资助金额:
    $ 40.5万
  • 项目类别:
Exosomes:From biogenesis and secretion to the early pathogenesis of Alzheimer's disease
外泌体:从生物发生和分泌到阿尔茨海默病的早期发病机制
  • 批准号:
    9421411
  • 财政年份:
    2017
  • 资助金额:
    $ 40.5万
  • 项目类别:
Exosomes:From biogenesis and secretion to the early pathogenesis of Alzheimer's disease
外泌体:从生物发生和分泌到阿尔茨海默病的早期发病机制
  • 批准号:
    10183120
  • 财政年份:
    2017
  • 资助金额:
    $ 40.5万
  • 项目类别:
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
  • 批准号:
    9258500
  • 财政年份:
    2016
  • 资助金额:
    $ 40.5万
  • 项目类别:
'Intranasal Insulin Therapy for HIV- Associated Neurocognitive Disorders'
“鼻内胰岛素治疗 HIV 相关神经认知障碍”
  • 批准号:
    9762158
  • 财政年份:
    2015
  • 资助金额:
    $ 40.5万
  • 项目类别:

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相似海外基金

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
  • 批准号:
    9258500
  • 财政年份:
    2016
  • 资助金额:
    $ 40.5万
  • 项目类别:
CD 8 T Cell Mediated Disruption of Blood Brain Tight Junction
CD 8 T 细胞介导的血脑紧密连接破坏
  • 批准号:
    8306282
  • 财政年份:
    2009
  • 资助金额:
    $ 40.5万
  • 项目类别:
CD 8 T Cell Mediated Disruption of Blood Brain Tight Junction
CD 8 T 细胞介导的血脑紧密连接破坏
  • 批准号:
    8509031
  • 财政年份:
    2009
  • 资助金额:
    $ 40.5万
  • 项目类别:
HIV, Drug Abuse and Neurotoxicity
艾滋病毒、药物滥用和神经毒性
  • 批准号:
    8051737
  • 财政年份:
    2009
  • 资助金额:
    $ 40.5万
  • 项目类别:
Neuron-Glia Mechanisms & Interactions Underlying Opioid Abuse-HIV-1 Comorbidity
神经元-胶质细胞机制
  • 批准号:
    8284484
  • 财政年份:
    2009
  • 资助金额:
    $ 40.5万
  • 项目类别:
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