Regulation of HIV latency by microglial-neuronal interactions
小胶质细胞-神经元相互作用对 HIV 潜伏期的调节
基本信息
- 批准号:10674037
- 负责人:
- 金额:$ 78.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalBiological ModelsBrainCRISPR/Cas technologyCX3CL1 geneCellsCerebrumCoculture TechniquesCollaborationsCommunicationDefectDevelopmentDrug abuseDrug usageEffector CellFractalkineGABA ReceptorGeneticGenetic TranscriptionGlutamate ReceptorHIVHIV InfectionsHIV SeropositivityHandHumanImaging technologyIndividualInfectionInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryInvestigationLaboratoriesLeadLibrariesMediatingMemoryMethamphetamineMicrogliaModelingMolecular BiologyMorbidity - disease rateMutationNatural ProductsNerve DegenerationNeurobiologyNeurocognitiveNeurogliaNeuronsOrganoidsPathway interactionsPatientsPattern recognition receptorPharmaceutical PreparationsProductionProductivityPurinoceptorRattusReceptor GeneReceptor SignalingRecoveryRegulationRestRiskRoleSignal PathwaySignal TransductionStressSymptomsSystemT-LymphocyteTestingTherapeuticUnited StatesViralViral ProteinsVirusantiretroviral therapycell transformationdesigndopaminergic neurondrug of abuseexperimental studygamma-Aminobutyric Acidgenome editingglial activationinduced pluripotent stem cellinhibitorknock-downmethamphetamine effectmethamphetamine exposuremigrationmortalitymultidisciplinaryneurocognitive disorderneurotoxicneurotransmissionnovelpharmacologicprotective effectreceptorreconstitutionresponsesmall hairpin RNAsubstance usetranscriptome sequencing
项目摘要
Summary
Over 40% of HIV-positive individuals in the United States engage in substance use. This
not only represents a major cause of enhanced morbidity and mortality, but also is associated
with increased risks of neurocognitive disorders, such as HAND. Neurons possess refined
systems for maintaining constant communication with glia through propagation of “Off” and “On”
signals controlling microglial activation states. Using HIV latency models in immortalized human
microglial cells (hµglia/HIV), we have shown previously that cellular activation and inflammatory
responses induce HIV production. Remarkably, co-culture of productively infected microglia with
an excess of healthy neurons leads to viral silencing. We have also shown that hµglia/HIV cells
can migrate into brain organoids where they become silenced. However, damaging neurons with
a variety of agents, including methamphetamine (METH), a frequently-used abuse substance
among HIV-infected individuals, produce reactivation signals for HIV, and this initiates a cycle of
microglial activation and further neuronal damage. This cycle of shutdown and reactivation seems
to parallel the M1 to M2 transition model of microglial cells, much as HIV latency in T cells is a
product of the natural transition of effector cells to resting memory cells. In this proposal, we seek
to define the key signals mediating the cycle of viral silencing and reactivation in microglial cells
by neurons in the context of iPSC-derived cerebral organoids. This multidisciplinary investigation
is designed as a close collaboration between the laboratories of Dr. Jonathan Karn (CWRU, HIV
molecular biology), Dr. Anthony Wynshaw-Boris (CWRU, iPSC cells, brain organoids), Dr. Kurt
Hauser (VCU, neurobiology and drug abuse), and Dr. Pamela Knapp (VCU, brain organoids). To
avoid the limitations of working with transformed cells, we have recently initiated experiments
using co-cultures between iPSC-derived cerebral organoids and microglia. Using co-cultures
between iPSC-derived cerebral organoids and microglia, we will thoroughly test the hypothesis
that the exaggerated responses of HIV-infected microglia to neuronal damage leads to enhanced
neurodegeneration. We will also test the hypothesis that exposure to METH, given this
background of faulty microglia-neuron crosstalk, enhances HIV replication. Using genome editing
approaches, we will identify the specific contribution of “On” and “Off” receptor systems in
controlling HIV latency in microglia, and study how METH impacts neuronal-microglial signaling
to augment HIV production. In parallel with our genetic investigations, we will also evaluate a
number of pharmacological agents against microglial receptors, HIV transcription inhibitors, and
mediators of inflammation in order to define therapeutic approaches that might be expected to
slow the development of HAND, especially in patients who abuse drugs.
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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JONATHAN KARN其他文献
JONATHAN KARN的其他文献
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{{ truncateString('JONATHAN KARN', 18)}}的其他基金
The role of RNA m6A modification in the regulation of HIV latency and reactivation
RNA m6A 修饰在调节 HIV 潜伏和再激活中的作用
- 批准号:
10600078 - 财政年份:2022
- 资助金额:
$ 78.49万 - 项目类别:
The role of RNA m6A modification in the regulation of HIV latency and reactivation
RNA m6A 修饰在调节 HIV 潜伏和再激活中的作用
- 批准号:
10461499 - 财政年份:2022
- 资助金额:
$ 78.49万 - 项目类别:
Research Support Core B: Primary Cell, Biomimetic, and iPSC-derived Cell Models
研究支持核心 B:原代细胞、仿生和 iPSC 衍生细胞模型
- 批准号:
10304584 - 财政年份:2021
- 资助金额:
$ 78.49万 - 项目类别:
Research Support Core B: Primary Cell, Biomimetic, and iPSC-derived Cell Models
研究支持核心 B:原代细胞、仿生和 iPSC 衍生细胞模型
- 批准号:
10632094 - 财政年份:2021
- 资助金额:
$ 78.49万 - 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
- 批准号:
10158438 - 财政年份:2019
- 资助金额:
$ 78.49万 - 项目类别:
Regulation of HIV latency by microglial-neuronal interactions
小胶质细胞-神经元相互作用对 HIV 潜伏期的调节
- 批准号:
10220927 - 财政年份:2019
- 资助金额:
$ 78.49万 - 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
- 批准号:
10403547 - 财政年份:2019
- 资助金额:
$ 78.49万 - 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
- 批准号:
10629307 - 财政年份:2019
- 资助金额:
$ 78.49万 - 项目类别:
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