The role of TFAM alterations in HIV- and ART-induced mitochondrial dysfunction in the brain
The role of TFAM alterations in HIV- and ART-induced mitochondrial dysfunction in the brain
批准号:
10536678
负责人:
Jerel Adam Fields
金额:
$39.5万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-01-01 至 2026-11-30
关键词:
Acquired Immunodeficiency SyndromeAcuteAddressAffectAgingAgonistAnti-Inflammatory AgentsAreaAstrocytesAutopsyBasic ScienceBehavioral SciencesBioenergeticsBiogenesisBrainBrain DiseasesBuffersChronicCognitiveDataDiseaseExcess MortalityExhibitsExposure toExtracellular SpaceGene ExpressionGeneticGlucoseGlutamineGlycolysisHIVHIV Envelope Protein gp120HIV InfectionsHIV-associated neurocognitive disorderHomeostasisHumanIn VitroInfectionInflammatoryInterleukinsLactate TransporterLearningLinkLocationMemoryMetabolicMetabolismMicrogliaMitochondriaMitochondrial ProteinsMusNeurodegenerative DisordersNeurologic DysfunctionsNeuronal DysfunctionNeuronsOxidative PhosphorylationPersonsPharmaceutical PreparationsPhasePhenotypePlayPrevalenceProcessProductionProteinsQuality of lifeReportingResearchResearch PriorityRoleSeminalSpecimenStimulusTenofovirTestingTherapeuticTransgenic MiceViralViral Load resultViral ProteinsVirusWorkantiretroviral therapybrain cellbrain tissuecannabinoid receptorcomorbiditycomparison controlcytokinein vitro Modelknock-downmind controlmitochondrial dysfunctionmonocytemortality riskmouse modelneuroinflammationneuronal metabolismneuropathologyneurotoxicneurotoxicityneurotrophic factornovel therapeutic interventionpreventrelease factortranscription factor
中文摘要
总结
英文摘要
SUMMARY
Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of
neurological dysfunction. Despite effective antiretroviral therapy (ART), treatments to reduce the prevalence of
HIV-associated neurocognitive disorder (HAND) are lacking. Recent findings suggest that increased
mitochondrial activity in reactive astroglia play a causal role in mitochondrial dysfunction in neurons and this may
be a targetable mechanism underlying neuronal dysfunction in virally suppressed people with HIV (PWH). Early
during HIV infection, HIV-infected monocytes enter the brain and spread infection to resident microglia that then
release HIV, HIV proteins, and inflammatory cytokines, all of which stimulate a proinflammatory phenotype in
astroglia. Reactive astroglia are a hallmark of postmortem brain tissues from PWH with HAND even when on
suppressive ART. Astroglia have many homeostatic functions, which are likely disrupted by chronic low-level
HIV infection and long-term exposure to ART. One such function of astroglia is to buffer the concentrations of
metabolic substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite
this crucial function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of
bioenergetic deficits during HAND, little is known about how these processes are affected in reactive astroglia.
We’ve recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and
secreting the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve
this increase in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factors
(TFAM), which is associated with a reduction in TFAM expression and viability in neurons. Importantly, this
neurotoxicity is blocked by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the
reactive phenotype of reactive astroglia. However, the mechanistic link between increased mitochondrial activity
in reactive astroglia and the reduction in mitochondrial biogenesis in neurons is not understood. We will
investigate the role of astroglial metabolism in HAND by testing the hypothesis that increased mitochondrial
activity in reactive astroglia compromises mitochondrial function in proximal neurons. AIM 1 will test in
human brain cells how TFAM knockdown alters mitochondrial activity in and neurotoxicity conferred by reactive
astroglia. AIM 2 will investigate in postmortem brain tissues from PWH with and without HAND and HIV- controls
the location and changes in mitochondrial biogenesis and dynamics factors and lactate transporters in reactive
astroglia and neurons. In AIM 3, mouse brains exposed to the HIV protein gp120 and ART drugs will be used to
investigate mitochondrial biogenesis and dynamics factors and lactate transporters in astroglia and neurons.
These AIMs address the Office of AIDS Research Priorities to 1) Address HIV-Associated Comorbidities; and 2)
Advance Cross-Cutting Areas of research in the basic and behavioral sciences.
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