NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl
批准号:
10402833
负责人:
Norman J Haughey
金额:
$60.23万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-01 至 2025-04-30
关键词:
AcuteAdherenceAnti-Retroviral AgentsAstrocytesBindingBiogenesisBiological ModelsBrainCapsid ProteinsCessation of lifeChronicComplementComplexCorpus striatum structureDendritic SpinesDisease ProgressionDrug AddictionEpidemicExcisionFentanylGeneral PopulationHIVHIV Envelope Protein gp120HeroinImpaired cognitionIn VitroInfectionInflammasomeInflammationInflammatoryInnate Immune SystemInterleukin-18IntoxicationLearningLeucine-Rich RepeatLiverMemoryMemory impairmentMetabolismMicrogliaModificationMorphineMusNeuronsNucleotidesOpioidPathway interactionsPattern recognition receptorPersonsPhagocytosisPharmaceutical PreparationsPhysiologicalPopulationPrimary Cell CulturesProteinsReactive Oxygen SpeciesRoleSelf AdministrationSynapsesSystemTestingTransgenic MiceTransgenic OrganismsUnited StatesUp-RegulationViralVirus Diseasesbiological adaptation to stresscognitive functioncomplement systemcytokinedensitydrug withdrawalextracellular vesiclesimmune functionimprovedin vivo Modelmarenostrinmorphine administrationneuron lossopioid abuseopioid useopioid withdrawaloxidationpreventrepairedresponsetat Protein
中文摘要
摘要
与未感染艾滋病毒的人群相比,艾滋病毒感染者(PLWH)的吸毒成瘾率更高,
通常表现出更快的疾病进展速度,包括早期和快速进展的认知障碍。
我们以前已经证明,急性吗啡给药引起的突触损伤,
戒毒期间的治疗这些修复机制在gp120转基因小鼠中并不活跃,
停药期间修复失败。尽管这些观察结果加上其他一些研究,
已经证明吗啡与HIV的相互作用最终会降低树突棘密度,
这些相互作用的机制尚不清楚。我们的初步发现表明最初的树突状细胞
吗啡诱导的损伤涉及非典型核苷酸结合寡聚化结构域的激活,
星形胶质细胞中富含亮氨酸的重复序列和含Pyrin结构域(NLRP)的炎性体通路,
携带补体C3的EV的释放。这种补体蛋白在树突棘和靶标中被调理
它们通过吞噬作用消除。吗啡的去除阻止了补体C3的脱落,
星形胶质细胞和树突棘可以自我修复。然而,在病毒感染的情况下,
小胶质细胞上模式识别受体的激活与经典NLRP的慢性激活
炎性体途径,维持持续炎症状态,这种慢性炎症状态
阻止树突棘自我修复在这里,我们建议使用原代细胞培养,EcoHIV感染的小鼠,
条件性转基因系统,以检验TLR、炎性小体和
补体系统参与阿片类药物滥用者的神经元损伤。
.
英文摘要
ABSTRACT
People living with HIV (PLWH) have higher rates of drug addiction compared with uninfected populations, and
often show faster rates of disease progression, including early and rapidly progressing cognitive impairments.
We have previously demonstrated that synaptic damage resulting from acute morphine administration self-
repairs during drug withdrawal. These repair mechanisms were not active in gp120 transgenic mice, and synaptic
repair failed during drug withdrawal. Although these observations in addition to a number of other studies that
have demonstrated interactions of morphine with HIV that ultimately reduce dendritic spine density, the precise
mechanisms for these interactions are not understood. Our preliminary findings suggests that the initial dendritic
damage induced by morphine involves activation of a non-canonical Nucleotide-binding oligomerization domain,
Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome pathway in astrocytes that facilitates
the release of EVs carrying complement C3. This complement protein is opsonized in dendritic spines and targets
them for elimination by phagocytosis. The removal of morphine stops the shedding of complement C3 from
astrocytes, and dendritic spines can self-repair. However, in the setting of viral infection there is a sustained
activation of pattern recognition receptors on microglia with chronic activation of the classical NLRP
inflammasome pathway that maintains a state of persistent inflammation, This chronic inflammatory state
disallows dendritic spines to self-repair. Here we propose to use primary cell culture, EcoHIV infected mice, and
conditional transgenic systems to test the hypothesis that interactions between TLRs, the inflammasome, and
the complement system contribute to neuronal damage in PLHW who abuse opiates.
.
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