Peptide therapy for alcohol-induced CNS injury
Peptide therapy for alcohol-induced CNS injury
批准号:
10572298
负责人:
Mohammed Abdul Muneer
金额:
$25.46万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2025-04-30
关键词:
ATF2 geneAlcohol abuseAlcohol consumptionAlcohol-Induced DisordersAlcoholsAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAnimalsAnti-Inflammatory AgentsAntioxidantsAnxietyApoptoticBehavioralBinding SitesBiochemicalBlood - brain barrier anatomyBrainBrain InjuriesCell DeathCellsCerebellumChIP-seqChronicChronic DiseaseClinicalCognitiveCognitive deficitsCytoprotectionDarknessDataDefense MechanismsDiseaseDrug Metabolic DetoxicationFeedbackFree RadicalsFunctional disorderGene ExpressionGene ProteinsGenesGenetic TranscriptionGoalsHeavy DrinkingHippocampusImpairmentInflammatoryInjectionsInvestigationKnock-outKnockout MiceKnowledgeLightMatrix MetalloproteinasesMediatingMemoryMemory impairmentMental DepressionMotorMultiple SclerosisMusNerve DegenerationNervous System TraumaNeurocognitive DeficitNeurologicNeurologic DeficitNuclearNuclear TranslocationNucleic Acid Regulatory SequencesOxidantsOxidative StressOxidative Stress InductionParkinson DiseasePathway interactionsPenetrationPeptidesPrefrontal CortexProteinsPsychological StressPublishingRecoveryRecovery of FunctionRegulationReportingResearch PersonnelResistanceResponse ElementsRoleSensorySignal PathwaySignal TransductionStrokeSucroseSystemTestingTherapeuticTherapeutic AgentsTherapeutic InterventionToxic effectTranscription CoactivatorTransforming Growth FactorsTraumatic Brain InjuryUnited StatesUp-RegulationWorkalcohol effectalcohol exposureantioxidant enzymebehavior testcentral nervous system injuryclinically relevantcognitive functioncohortdrug of abusegene interactionin vivoneuralneuroinflammationneuron lossneuropathologyneuroprotectionnew therapeutic targetnoveloxidative damagepreferencepreventproblem drinkerpsychologicremediationrepairedresponsesubcutaneoustherapeutic targettranscription factor
中文摘要
摘要
英文摘要
ABSTRACT
Alcohol is the most used and abused drug in the United States. Chronic alcohol abuse results in neuronal
degeneration and functional deficits in sensorimotor, memory, psychological, and cognitive functions. We and
others have demonstrated that oxidative signaling is the central mechanism in alcohol-induced injury that leads
to neurological and functional deficits. Remediation of accumulating oxidative radicals may serve as an
effective strategy for preventing the progression of neurological damage in alcoholics. Thus, this proposal will
study a novel hypothesis that the brain injury and associated neuroinflammation and neurodegeneration
caused by alcohol-induced oxidative damage can be repaired by activating the antioxidant signaling Nrf2
(nuclear factor E2-related factor 2) pathway. The Nrf2 transcriptional system is an endogenous defense
mechanism that boosts the expression of many detoxifying, cytoprotective and anti-inflammatory genes by
interacting with the antioxidant response element (ARE) in their regulatory regions. Nrf2 has the potential to be
a novel and therapeutic target to mitigate alcohol-induced neural damage. Our central hypothesis is that
activation of antioxidant-promoting transcription factor Nrf2 alleviates oxidative stress-induced
pathophysiological changes associated with excessive alcohol ingestion. These changes include activation of
transforming growth factor β1 (TGF-β1) and matrix metalloproteinases (MMPs), neuroinflammatory responses,
and neurodegeneration. Activation of Nrf2 transcription factor and up-regulation of endogenous antioxidant
enzymes will be achieved by treating animals with Nrf2 activator III TAT peptide (Nrf2 peptide). We will
administer Nrf2 peptide to the alcohol ingested mice systemically (subcutaneous) and evaluate its therapeutic
potential in alleviating alcohol-associated neurological impairments in defined regions such as the prefrontal
cortex, hippocampus, and cerebellum. The proposed study not only validates the cause and effect of Nrf2
peptide in mitigating oxidative stress in AUD but also identifies the mechanistic regulation of Nrf2 transcription
factor activated antioxidant genes and their interactions with Nrf2 by ChIP-qPCR, and ChIP-Seq. The
protective role of Nrf2 will be determined by assessing its effects on gene expression and protein levels of the
major antioxidant, inflammatory, and apoptotic proteins. We will validate the effect of Nrf2 peptide in Nrf2
knock-out (KO) mice (Nrf2−/−). We will also use a cohort of behavioral tests that will utilize to assess cognitive,
sensory-motor feedback, and psychological behavioral recovery associated with Nrf2 peptide treatment
following alcohol exposure in wild type and Nrf2-/- mice. We will compare the results with control peptide
(random sequence with TAT) treated animals. We anticipate that the findings from this study will have
extensive clinical relevance.
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