Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection
HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制
基本信息
- 批准号:10266139
- 负责人:
- 金额:$ 70.45万
- 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
- 起止时间:2020-09-30 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:2-arachidonylglycerolAberrant DNA MethylationAcuteAffectAgonistAlzheimer&aposs DiseaseAnti-Inflammatory AgentsAntiinflammatory EffectApoptosisAttention ConcentrationAttenuatedAutopsyBasal GangliaBloodBrainCASP1 geneCNR1 geneCNR2 geneCXCL10 geneCannabidiolCannabinoidsCellsCerebrospinal FluidChronicCpG IslandsDNADNA MethylationDataDecision MakingDevelopmentDiseaseDisease ProgressionEndocannabinoidsEndoplasmic ReticulumEpigenetic ProcessEpithelialEthanolaminesEventGene ExpressionGenerationsGenesHIVHIV-associated neurocognitive disorderHeat shock proteinsHeritabilityIRF1 geneImmunologicsInfectionInflammasomeInflammationInflammatoryInflammatory ResponseInterferonsIntestinesKnowledgeLipidsLongevityLysineMacacaMacaca mulattaMeasuresMediatingMediator of activation proteinMemoryMental DepressionMicroRNAsMicrogliaMitosisMolecularMovementMultiple SclerosisNatureNeuraxisNeurodegenerative DisordersNeuronal DysfunctionNeuronsOxidative StressOxidoreductasePPAR gammaParkinson DiseasePathogenesisPatientsPenetrationPeripheralPharmaceutical PreparationsPlayProductionProteinsResearchResidual stateRiskRoleSIVSTAT2 geneSerum MarkersSignal TransductionSiteSymptomsTRPV1 geneTestingTetrahydrocannabinolTherapeuticTimeUp-RegulationViralViral reservoirVirus ReplicationWFS1 geneWolfram Syndromeantiretroviral therapycannabinoid treatmentchemokinecombinatorialcomorbiditycrystallin mucytokinedaughter cellds-DNAendocannabinoid signalingendogenous cannabinoid systemendoplasmic reticulum stressfatty acid amide hydrolaseimmune activationimmune functionimmunoregulationinnovationlymph nodesmRNA Expressionmonocytenervous system disorderneuroinflammationpreventpromoterprotein expressionreceptorresponsesimian human immunodeficiency virus
项目摘要
ABSTRACT
HIV associated neurological disorder (HAND), a major comorbidity affecting about 30-50% of patients receiving
suppressive anti-retroviral therapy is characterized by difficulties with attention, concentration, decision making
and memory, depression and slowed movements. Although chronic activation of brain microglia is proposed to
drive HAND, the molecular mechanisms remain ill defined. Emerging evidence has shown that epigenetic
mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of multiple
sclerosis, Parkinson’s and Alzheimer’s disease. Nevertheless, the role of DNA methylation specifically in HIV
induced monocyte/microglia activation remains unknown. The fact that epigenetic marks are heritable and
passed on to several generations of daughter cells during mitosis might explain a potential mechanism causing
monocyte/microglial activation that may in turn help maintain persistent neuroinflammation in cART treated
patients. Our preliminary studies identified significant upregulation of proinflammatory interferon stimulated and
chemokine genes in basal ganglia and marked alterations in DNA methylation of CpG islands in promoters of
genes associated with inflammatory response, apoptosis, dsDNA damage response and oxidative stress in
colonic epithelium of chronically SIV-infected macaques, respectively. More importantly, chronic cannabinoid
treatment to ART naïve SIV-infected rhesus macaques prevented proinflammatory gene expression in brain and
epigenetic alterations suggesting their immense therapeutic potential for attenuating neuroinflammation and
reduced HAND related symptoms. In the proposed studies, we will for the first time investigate changes in DNA
methylation associated with delta-9-tetrahydrocannabinol (THC), cannabidiol, JWH133 (CB2R agonist) induced
suppression of monocyte/microglial activation through the course of SIV infection. Further, we will determine the
effect of combination anti-retroviral treatment (cART) in conjunction with chronic cannabinoid treatments on
epigenetic alterations, viral reservoir, inflammation and endogenous cannabinoid levels in the blood and
cerebrospinal fluid. Finally, we will investigate the receptor mediated and molecular mechanisms by which THC
blocks endoplasmic reticulum stress, a key event in the onset of neurodegenerative diseases. The proposed
research is highly innovative and applies state of the art immunological and molecular approaches to fill a
significant gap in our understanding of the epigenetic mechanisms associated with HAND. As cannabinoids have
shown great promise for the treatment of neurological disorders, the proposed studies are necessary, as it will
provide a fundamental understanding of the epigenetic and endocannabinoid mechanisms underlying their anti-
inflammatory effects. Finally, the results will have important therapeutic implications for immune modulation in
not only HIV but also other chronic neuroinflammatory diseases.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Siddappa N Byrareddy其他文献
Identification and Biological Characterization of Unique B/C Recombinant Strains of HIV-1 In Southern States of India
- DOI:
10.1186/1742-4690-2-s1-p126 - 发表时间:
2005-12-08 - 期刊:
- 影响因子:3.900
- 作者:
Siddappa N Byrareddy;PK Dash;A Mahadevan;Anita Desai;N Jayasuryan;P Satishchandra;V Ravi;SK Shankar;U Ranga - 通讯作者:
U Ranga
Immunological insights into the re-emergence of human metapneumovirus
对人偏肺病毒再次出现的免疫学见解
- DOI:
10.1016/j.coi.2025.102562 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:5.800
- 作者:
Arpan Acharya;Siddappa N Byrareddy - 通讯作者:
Siddappa N Byrareddy
Siddappa N Byrareddy的其他文献
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{{ truncateString('Siddappa N Byrareddy', 18)}}的其他基金
Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV
使用 CAR/CXCR5 T 细胞靶向 CNS 储存库以长期缓解 HIV
- 批准号:
10475466 - 财政年份:2022
- 资助金额:
$ 70.45万 - 项目类别:
Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV
使用 CAR/CXCR5 T 细胞靶向 CNS 储存库以长期缓解 HIV
- 批准号:
10677645 - 财政年份:2022
- 资助金额:
$ 70.45万 - 项目类别:
Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection
HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制
- 批准号:
10434910 - 财政年份:2020
- 资助金额:
$ 70.45万 - 项目类别:
Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection
HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制
- 批准号:
10656263 - 财政年份:2020
- 资助金额:
$ 70.45万 - 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
- 批准号:
9891944 - 财政年份:2017
- 资助金额:
$ 70.45万 - 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
- 批准号:
9450468 - 财政年份:2017
- 资助金额:
$ 70.45万 - 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
- 批准号:
9349159 - 财政年份:2017
- 资助金额:
$ 70.45万 - 项目类别:
Targeting gut-brain axis to eliminate CNS reservoirs
瞄准肠脑轴消除中枢神经系统储库
- 批准号:
9350887 - 财政年份:2017
- 资助金额:
$ 70.45万 - 项目类别:
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