A new pathway of spinal neurons in neuropathic pain induced by HIV with opioid
脊髓神经元在 HIV 和阿片类药物诱导的神经性疼痛中的新通路
基本信息
- 批准号:10217077
- 负责人:
- 金额:$ 34.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmericanApplications GrantsAreaBindingBiological AssayBromodomainCapsid ProteinsCellsChromatinChronicClinical DataComplicationDataDeacetylaseDevelopmentDrug Metabolic DetoxicationEconomicsEnhancersEpidemicEpigenetic ProcessFunctional disorderGene ExpressionGenesGenetic TranscriptionHIVHIV Envelope Protein gp120HIV InfectionsHIV neuropathyHIV-1HealthHeroinHistone H3HumanImageImmuneImpairmentIndividualKnockout MiceLinkLongevityMediatingMitochondriaModelingMolecularMorphineNational Institute of Drug AbuseNervous System PhysiologyNeuraxisNeurogliaNeurologicNeurologic DeficitNeuronsOpioidOpioid AnalgesicsOxidative StressPainPainlessPathway interactionsPatientsPharmacologyPlayProductionProtein FamilyPublic HealthReaderResearchResearch PersonnelResearch Project GrantsRoleSeveritiesSignal TransductionSignal Transduction PathwaySirtuinsSocietiesSpinal cord posterior hornSuperoxidesSystemTNF geneTestingTherapeutic InterventionUnited StatesUp-RegulationViral VectorVirus Diseasesantiretroviral therapybasec-myc Geneschronic painconditional knockoutcytokinedrug of abuseeconomic costglobal healthhistone methylationin vivoinsightinterestmechanical allodynianeuroinflammationneuron lossneuronal circuitryneurotoxicneurotoxicityneurotransmissionnovelnovel therapeuticsopioid abuseopioid epidemicopioid overusepainful neuropathypromoterreceptorresponsespinal pathwaytranscription factor
项目摘要
Project Summary:
In response to the RFA-MH-18-610---“the FOA invites research grant applications to decipher pathways and
mechanisms responsible for HIV-1 induced central nervous system (CNS) dysfunction”, we focused on
the Areas of Research Interest: “NIDA is interested in understanding the underlying mechanisms whereby
drugs of abuse and HIV infection interact to impair CNS functions mediated through altered neuronal circuits,
neuronal receptors.” The United States currently has an opioid overuse epidemic. Despite the advent of
effective anti-retroviral therapy, HIV-neuropathic pain (HIV-NP) is a common neurological complication as
patients enjoy longer life spans. This serious health issue is further exacerbated by chronic abuse of opiates
often seen in HIV+ individuals, leading, in turn, to increased severity of neurological deficits. HIV and chronic
morphine use/abuse can increase cytokine production resulting in enhanced neuroinflammation. HIV-related
neuron damage is induced either directly by neurotoxic substances or indirectly by activating glial cells
releasing neurotoxic factors (such as, TNFα). Our preliminary data shows that repeated exposure of HIV coat
protein gp120 with morphine decreased neuronal sirtuin (SIRT) 3 expression, an NAD+-dependent
deacetylase that regulates mitochondrial detoxification in the spinal cord dorsal horn (SCDH), and increased
in neuronal mitochondrial superoxide. However, the exact upstream pathways responsible for the loss of
neuronal SIRT3 in the SCDH in the interaction of gp120 and morphine is not clear. Recent studies show that
the epigenetic reader Brd4, one of bromodomain and extraterminal (BET) family of proteins modulates, the
expression of transcriptional factor c-Myc. The epigenetic writer, enhancer of zeste homology 2 (EZH2)
suppresses gene expression via histone methylation (e.g., H3K27me3). Brd4 positively regulates EZH2
transcription through upregulation of c-Myc. In this proposal we will test the hypothesis that neuronal TNFRI-
--Brd4---c-Myc---EZH2 epigenetic pathway mediates the loss of anti-oxidative SIRT3 system in the spinal
cord dorsal horn in HIV/chronic opioid-related neuropathic pain. We will combine molecular and epigenetic
approach, knockout (KO) mice, conditional knockout (cKO) mice, neuron-selective viral vectors,
mitochondrial superoxide imaging, and molecular-pharmacological assays all in vivo to prove novel
mechanisms. Based on the neuronal signal transduction pathway, the results of these studies will provide
insights on the treatment of neuropathic pain of the interaction of HIV and opioids.
项目总结:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SHUANGLIN HAO其他文献
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{{ truncateString('SHUANGLIN HAO', 18)}}的其他基金
The molecular mechanisms of astrocytes-neurons interaction in the morphine use disorder
吗啡使用障碍中星形胶质细胞-神经元相互作用的分子机制
- 批准号:
10487821 - 财政年份:2022
- 资助金额:
$ 34.54万 - 项目类别:
Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy
肠道微生物组在 HIV/阿片类药物引起的周围神经病变中的作用
- 批准号:
10407591 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy
肠道微生物组在 HIV/阿片类药物引起的周围神经病变中的作用
- 批准号:
10163152 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
A new pathway of spinal neurons in neuropathic pain induced by HIV with opioid
脊髓神经元在 HIV 和阿片类药物诱导的神经性疼痛中的新通路
- 批准号:
10454144 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy
肠道微生物组在 HIV/阿片类药物引起的周围神经病变中的作用
- 批准号:
9920704 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
A new pathway of spinal neurons in neuropathic pain induced by HIV with opioid
脊髓神经元在 HIV 和阿片类药物诱导的神经性疼痛中的新通路
- 批准号:
9788388 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
A new pathway of spinal neurons in neuropathic pain induced by HIV with opioid
脊髓神经元在 HIV 和阿片类药物诱导的神经性疼痛中的新通路
- 批准号:
9978798 - 财政年份:2018
- 资助金额:
$ 34.54万 - 项目类别:
Neuropathic mechanisms and gene therapy on opioid dependence
阿片类药物依赖的神经病理机制和基因治疗
- 批准号:
8631473 - 财政年份:2014
- 资助金额:
$ 34.54万 - 项目类别:
Neuropathic mechanisms and gene therapy on opioid dependence
阿片类药物依赖的神经病理机制和基因治疗
- 批准号:
9031097 - 财政年份:2014
- 资助金额:
$ 34.54万 - 项目类别:
Neuropathic mechanisms and gene therapy on opioid dependence
阿片类药物依赖的神经病理机制和基因治疗
- 批准号:
9247160 - 财政年份:2014
- 资助金额:
$ 34.54万 - 项目类别:
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