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Cell intrinsic and extrinsic effects of zinc metabolism in therapy resistant melanoma
Organization UNIVERSITY OF PITTSBURGH AT PITTSBURGHLocation PITTSBURGH, UNITED STATESPosted 1 Apr 2025Deadline 1 Sept 2025 โ ๏ธ
NIHUS FederalResearch GrantFY2025AddressAffectAldesleukin GeneAutomobile DrivingAutoregulationBiological Response ModifiersBiomodulatorsCD8CD8 CellCD8 T cellsCD8 lymphocyteCD8+ T cellCD8+ T-LymphocyteCD8-Positive LymphocytesCD8-Positive T-LymphocytesCD8BCD8B1CD8B1 geneCDK4ICDKN2CDKN2 GenesCDKN2ACDKN2A geneCMM2CRG-2CRISPRCRISPR editing screenCRISPR screenCRISPR-based screenCRISPR/Cas systemCRISPR/Cas9 screenCXCL10CXCL10 geneCancer PatientCancersCell BodyCell CommunicationCell Communication and SignalingCell CycleCell Division CycleCell InteractionCell SignalingCell membraneCell-to-Cell InteractionCellsCessation of lifeChemotactic CytokinesClustered Regularly Interspaced Short Palindromic RepeatsCyclin-Dependent Kinase Inhibitor 2A GeneCytoplasmic MembraneDataDeathDevelopmentDietDietary ZincDown-RegulationExhibitsExtravasationFoundationsFutureGene TranscriptionGenetic TranscriptionGoalsHomeostasisHomologous Chemotactic CytokinesHumanIFI10IL-2 GeneIL2IL2 geneINK4INK4AINP10IP-10ImmuneImmune MediatorsImmune Mediators/ModulatorsImmune mediated therapyImmunesImmunologically Directed TherapyImmunotherapyImpairmentInfiltrationInflammatoryIntercrinesInterleukin 2 Precursor GeneInterleukin-2 GeneIntermediary MetabolismIntracellular Communication and SignalingKnock-outKnockoutKnowledgeLYT3LeakageMHC ReceptorMOB-1MTS1MTS1 GenesMajor Histocompatibility Complex ReceptorMalignant CellMalignant MelanomaMalignant NeoplasmsMalignant Skin NeoplasmMalignant TumorMediatingMelanomaMelanoma CellMelanoma TumorMelanoma patientMetabolicMetabolic ProcessesMetabolismMitochondrial DNAModern ManMolecularOutcomePD-1 antibodyPD1 antibodyPatientsPhysiological HomeostasisPlasma MembranePositionPositioning AttributePre-Clinical ModelPreclinical ModelsPrevalenceRNA ExpressionReceptor ActivationRegulationResearchResistanceRoleSCYB10SIS cytokinesSignal TransductionSignal Transduction SystemsSignalingSkin CancerSpillageStimulator of Interferon GenesStructureT-Cell Antigen ReceptorsT-Cell Growth Factor GeneT-Cell ReceptorT-CellsT-LymphocyteT8 CellsT8 LymphocytesTCGF GeneTP16TSG9ATeff cellTestingTherapeuticTranscriptionTumor growth in melanomaZincZinc decreasedZinc deficiencyZinc lowZn deficiencyZn elementZn levels lowZn++ lowaPD-1aPD1anti programmed cell death 1anti-PD-1anti-PD-1 Abanti-PD-1 antibodiesanti-PD-1 monoclonal antibodiesanti-PD1anti-PD1 Abanti-PD1 antibodiesanti-PD1 monoclonal antibodiesanti-programmed cell death protein 1anti-programmed cell death protein 1 antibodiesanti-programmed death-1 antibodyantiPD-1attenuationbiological signal transductioncGAMP STINGcGAMP-STINGcGAMP/STINGcGAS/STINGcancer cellcancer microenvironmentcheck point blockadecheckpoint blockadechemoattractant cytokinechemokineclinical relevanceclinically relevantclustered regularly interspaced short palindromic repeats screencyclic GMP-AMP synthase/STINGcytotoxicdata miningdataminingdevelopmentaldietsdrivingeffector T cellextracellulargIP-10immune check point blockadeimmune checkpoint blockadeimmune therapeutic approachimmune therapeutic interventionsimmune therapeutic regimensimmune therapeutic strategyimmune therapyimmune-based therapiesimmune-based treatmentsimmuno therapyimprovedimproved outcomein vivoinsightknock-downknockdownlow Zinc levelmalignancymalignant skin tumormelanoma cancer modelmelanoma modelmelanoma tumor modelmitochondria fitnessmitochondrial fitnessmouse modelmtDNAmurine modelneoplasm/cancernew therapeutic approachnew therapeutic interventionnew therapeutic strategiesnew therapy approachesnew treatment approachnew treatment strategynovel therapeutic approachnovel therapeutic interventionnovel therapeutic strategiesnovel therapy approachp14ARFp16 Genesp16INK4 Genesp16INK4A Genesp16INK4apatient populationpatients suffering from melanomapatients with melanomaplasmalemmapreventpreventingrecruitresistance to therapyresistantresistant to therapyresponseresponse to therapyresponse to treatmentscRNA sequencingscRNA-seqsingle cell RNA-seqsingle cell RNAseqsingle cell expression profilingsingle cell transcriptomic profilingsingle-cell RNA sequencingsocial rolestandard of caretherapeutic outcometherapeutic resistancetherapeutic responsetherapy outcometherapy resistanttherapy responsethymus derived lymphocytetreatment resistancetreatment responsetreatment responsivenesstreatment strategytumortumor microenvironmentuptakezinc binding ligandzinc transporterzinc-binding proteinฮฑPD-1ฮฑPD1
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Project Summary/Abstract
The ultimate goal of this proposal is to address the fundamental gap in knowledge on the mechanisms driving
resistance to immune checkpoint blockade (ICB), particularly in melanoma patients who exhibit downregulation
or deletion of p16 (~40% of cases). The research plan focuses on elucidating the mechanistic role of p16โฆ
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