2024
Effect of IL-6R blockade on plasma lipids and clinical outcomes among hospitalized patients with COVID-19 infection
Mohammadi K, Sleeman M, Boyapati A, Bigdelou P, Geba G, Fazio S. Effect of IL-6R blockade on plasma lipids and clinical outcomes among hospitalized patients with COVID-19 infection. Journal Of Lipid Research 2024, 65: 100568. PMID: 38795859, PMCID: PMC11237931, DOI: 10.1016/j.jlr.2024.100568.Peer-Reviewed Original ResearchPlasma lipid changesIL-6R blockadePlasma lipid levelsCOVID-19 pneumoniaClinical outcomesLDL-CHDL-CLipid levelsLipid changesSystemic infectionIL-6-mediated inflammationDay 7Moderately elevated triglyceridesInfluence plasma lipid levelsBaseline lipid levelsLDL-C levelsAbnormal lipid levelsAnti-inflammatory interventionsIL-6RLower LDL-CAcute systemic infectionNo significant associationPost hoc analysisInterleukin-6 receptorStudy therapyDifferential Regulation of the Type 2 Cytokines, IL-4 and IL-13, and the Alarmins, IL-33 and TSLPA, in Airway Inflammation and Remodeling
Asrat S, Srivatsan S, Buonagurio B, Nagashima K, Scott G, Gayvert K, Lim W, Ben L, Le Floc’h A, Murphy A, Sleeman M, Orengo J. Differential Regulation of the Type 2 Cytokines, IL-4 and IL-13, and the Alarmins, IL-33 and TSLPA, in Airway Inflammation and Remodeling. 2024, a3276-a3276. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a3276.Peer-Reviewed Original ResearchThe High Affinity Anti-IL-33 Antibody Itepekimab Potently Blocks IL-33 Induced Activation of the ST2/IL-1RAcP Signaling Complex and Inhibits Key Mediators of Airway Inflammation
Asrat S, Zhou Y, Rafique A, Kamat V, Scott G, Birchard D, Ben L, Murphy A, Franklin M, Sleeman M, Orengo J. The High Affinity Anti-IL-33 Antibody Itepekimab Potently Blocks IL-33 Induced Activation of the ST2/IL-1RAcP Signaling Complex and Inhibits Key Mediators of Airway Inflammation. 2024, a6989-a6989. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6989.Peer-Reviewed Original ResearchSimultaneous Blockade of IL-4 and IL-13 Signaling With Dupilumab Attenuates Type 2 Inflammation and Airway Remodeling in a Mouse Model of Severe Airway Disease
Asrat S, Scott G, Srivatsan S, Ben L, Birchard D, Lim W, Nagashima K, Le Floc'h A, Allinne J, Murphy A, Sleeman M, Orengo J. Simultaneous Blockade of IL-4 and IL-13 Signaling With Dupilumab Attenuates Type 2 Inflammation and Airway Remodeling in a Mouse Model of Severe Airway Disease. 2024, a5387-a5387. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a5387.Peer-Reviewed Original ResearchIntranasal Allergen Exposure Drives Lymphoid Aggregate Formation, Local Class-switching and Ige + Plasma Cell Accumulation in the Lung
Vecchione A, Garcia E, Srivatsan S, Sandén C, Erjefalt J, Murphy A, Sleeman M, Limnander A, Asrat S, Orengo J. Intranasal Allergen Exposure Drives Lymphoid Aggregate Formation, Local Class-switching and Ige + Plasma Cell Accumulation in the Lung. 2024, a6992-a6992. DOI: 10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6992.Peer-Reviewed Original ResearchDivergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse
Smagris E, Shihanian L, Mintah I, Bigdelou P, Livson Y, Brown H, Verweij N, Hunt C, Johnson R, Greer T, Hartford S, Hindy G, Sun L, Nielsen J, Halasz G, Lotta L, Murphy A, Sleeman M, Gusarova V. Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse. PLOS Genetics 2024, 20: e1011179. PMID: 38437227, PMCID: PMC10939284, DOI: 10.1371/journal.pgen.1011179.Peer-Reviewed Original ResearchConceptsAssociation studiesExome-wide association studyHuman genome-wide association studiesGenome-wide association studiesLoss of function variantsFamily enzymesMissense variantsObserved phenotypesFunctional variantsAberrant localizationProtein instabilityAncestry groupsHepatic triglyceride accumulationDivergent rolesLiver phenotypePhysiological functionsTriglyceride accumulationPhenotypeDeletionMouse liverIn vitro studiesHepatic cellsProteinEnzymeKnockout micePerturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis
Zhou Y, Zhao Y, Carbonaro M, Chen H, Germino M, Adler C, Ni M, Zhu Y, Kim S, Altarejos J, Li Z, Burczynski M, Glass D, Sleeman M, Lee A, Halasz G, Cheng X. Perturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis. Metabolism 2024, 154: 155830. PMID: 38428673, DOI: 10.1016/j.metabol.2024.155830.Peer-Reviewed Original ResearchWnt target genesWnt signalingGene expressionActivate gene expressionLiver zonationAlteration of Wnt signalingMouse NASH modelNon-alcoholic steatohepatitisSuppress gene expressionGene expression levelsNon-alcoholic steatohepatitis liversWnt regulationMetabolic pathwaysMetabolic zonationGenesRSPO3 expressionSpatial transcriptomicsIn situ hybridizationSpatial expressionExpression levelsRSPO3Perivenous hepatocytesMouse model of non-alcoholic steatohepatitisZonationModel of non-alcoholic steatohepatitis
2023
Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency
Altarejos J, Pangilinan J, Podgrabinska S, Akinci B, Foss-Freitas M, Neidert A, Ray Y, Zheng W, Kim S, Kamat V, Huang M, Min S, Mastaitis J, Dominguez-Gutierrez G, Kim J, Stevis P, Huang T, Zambrowicz B, Olson W, Godin S, Bradley E, Gewitz A, Baker M, Hench R, Davenport M, Chenevert T, DiPaola F, Yancopoulos G, Murphy A, Herman G, Musser B, Dansky H, Harp J, Gromada J, Sleeman M, Oral E, Olenchock B. Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. Science Translational Medicine 2023, 15: eadd4897. PMID: 37992152, DOI: 10.1126/scitranslmed.add4897.Peer-Reviewed Original ResearchConceptsLeptin concentrationsBody weightHepatic steatosisAdipose-derived hormone leptinClass 3 obesityCompassionate use treatmentHigher baseline leptinLeptin knockout miceAcceptable safety profileLower leptin concentrationsPresence of leptinHuman monoclonal antibodyLeptin receptor signalingTreatment of individualsPhase 1Baseline leptinLepr signalingLeptin deficiencyMetabolic sequelaeLiver diseaseClinical benefitSafety profileInsulin resistanceBlood glucoseInsulin sensitivity208 IL-4 and IL-13 drive distinct and overlapping disease-associated signatures in cell types relevant to atopic dermatitis
Srivatsan S, Buonagurio B, Nagashima K, Asrat S, Lim W, Le Floc’h A, Garcia M, Zamolodchikov D, Ajithdoss D, Alessandri-Haber N, Murphy A, Sleeman M, Orengo J. 208 IL-4 and IL-13 drive distinct and overlapping disease-associated signatures in cell types relevant to atopic dermatitis. Journal Of Investigative Dermatology 2023, 143: s367. DOI: 10.1016/j.jid.2023.09.216.Peer-Reviewed Original ResearchPharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis
Lawler P, Manvelian G, Coppi A, Damask A, Cantor M, Ferreira M, Paulding C, Banerjee N, Li D, Jorgensen S, Attre R, Carey D, Krebs K, Milani L, Hveem K, Damås J, Solligård E, Stender S, Tybjærg-Hansen A, Nordestgaard B, Hernandez-Beeftink T, Rogne T, Flores C, Villar J, Walley K, Liu V, Fohner A, Lotta L, Kyratsous C, Sleeman M, Scemama M, DelGizzi R, Pordy R, Horowitz J, Baras A, Martin G, Steg P, Schwartz G, Szarek M, Goodman S. Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis. Critical Care Explorations 2023, 5: e0997. PMID: 37954898, PMCID: PMC10635596, DOI: 10.1097/cce.0000000000000997.Peer-Reviewed Original ResearchProprotein convertase subtilisin/kexin type 9Convertase subtilisin/kexin type 9Subtilisin/kexin type 9Human cohort studiesODYSSEY OUTCOMESCohort studyType 9Isotype-matched controlExperimental murine modelSepsis ratePCSK9 inhibitionPCSK9 inhibitorsSepsis complicationsSepsis mortalitySepsis outcomeImproved survivalBacterial sepsisClinical outcomesBloodstream clearanceSepsis modelClinical trialsOdds ratioCardiovascular diseasePretreatment settingSepsis diagnosis
2008
Increased fear‐ and stress‐related anxiety‐like behavior in mice lacking tuberoinfundibular peptide of 39 residues
Fegley DB, Holmes A, Riordan T, Faber CA, Weiss JR, Ma S, Batkai S, Pacher P, Dobolyi A, Murphy A, Sleeman MW, Usdin TB. Increased fear‐ and stress‐related anxiety‐like behavior in mice lacking tuberoinfundibular peptide of 39 residues. Genes Brain & Behavior 2008, 7: 933-942. PMID: 18700839, PMCID: PMC2605196, DOI: 10.1111/j.1601-183x.2008.00432.x.Peer-Reviewed Original ResearchConceptsAnxiety-like behaviorAnxiety-related behaviorTuberoinfundibular peptideElevated plus-maze assayParathyroid hormone 2 receptorMedial paralemniscal nucleusGreater anxiety-like behaviorPavlovian fear conditioning paradigmShock-probe testGroups of neuronsMedial prefrontal cortexSubparafascicular areaNeurons projectAnxiety-related phenotypesLateral brainstemParalemniscal nucleusLateral septumBed nucleusStria terminalisFear conditioning paradigmEnvironmental provocationTargeted null mutationBrain regionsFear extinctionPrefrontal cortexThe CAMplexities of Central Ghrelin
Sleeman MW, Latres E. The CAMplexities of Central Ghrelin. Cell Metabolism 2008, 7: 361-362. PMID: 18460326, DOI: 10.1016/j.cmet.2008.04.009.Peer-Reviewed Original ResearchHypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin
López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Álvarez C, Gallego R, Lelliott CJ, Carling D, Tschöp MH, Diéguez C, Vidal-Puig A. Hypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin. Cell Metabolism 2008, 7: 389-399. PMID: 18460330, DOI: 10.1016/j.cmet.2008.03.006.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein Kinase KinasesAnimalsBlotting, WesternCarnitine O-PalmitoyltransferaseFas ReceptorFastingFatty Acid SynthasesFatty AcidsFeeding BehaviorGhrelinHypothalamusIn Situ HybridizationLeptinMaleMalonyl Coenzyme AMiceMice, Inbred C57BLMice, KnockoutMice, ObesePhosphorylationProtein KinasesRatsRats, Sprague-DawleyConceptsHypothalamic fatty acid metabolismFatty acid metabolismFatty acid synthaseAcid metabolismCarnitine palmitoyltransferase 1 activityFatty acid biosynthesisRegion-specific mannerGhrelin's effectsOrexigenic responseHypothalamic levelOrexigenic actionVentromedial nucleusFood intakeCurrent evidenceFAS expressionGhrelinAcid biosynthesisRelevant regulatory systemGenetic approachesProtein kinaseAMPK activityAcid synthaseSpecific inhibitionRegulatory systemPhysiological mechanismsThe mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome
Raz R, Stricker S, Gazzerro E, Clor JL, Witte F, Nistala H, Zabski S, Pereira RC, Stadmeyer L, Wang X, Gowen L, Sleeman MW, Yancopoulos GD, Canalis E, Mundlos S, Valenzuela DM, Economides AN. The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome. Development 2008, 135: 1713-1723. PMID: 18353862, DOI: 10.1242/dev.015149.Peer-Reviewed Original ResearchAbnormalities, MultipleAnimalsBody Mass IndexBone Morphogenetic ProteinsFertilityGenes, RecessiveGrowth Differentiation Factor 5HumansJointsLimb Deformities, CongenitalMaleMiceMice, Mutant StrainsMusculoskeletal AbnormalitiesMutationReceptor Protein-Tyrosine KinasesReceptor Tyrosine Kinase-like Orphan ReceptorsSyndrome
2007
Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
Pfluger PT, Kirchner H, Günnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE, Sleeman MW, Tschöp M. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. AJP Gastrointestinal And Liver Physiology 2007, 294: g610-g618. PMID: 18048479, DOI: 10.1152/ajpgi.00321.2007.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAnthropometryBlood GlucoseBody CompositionBody TemperatureBody WeightEatingEnergy MetabolismGene DeletionGenotypeGhrelinGlucose Tolerance TestInsulin ResistanceLigandsLipidsMiceMice, KnockoutMotor ActivityReceptors, GhrelinReverse Transcriptase Polymerase Chain ReactionRNA, MessengerConceptsFood intakeSimultaneous deletionStandard dietHigh-fat diet-induced obesityMotor activityWild-type control miceFirst mouse mutantsMetabolic phenotypeDiet-induced obesityEnergy metabolism phenotypesEnergy expenditureGene-deficient miceKnockout mice exhibitSingle gene-deficient miceSame genetic backgroundMost speciesWT miceControl miceStandard chowMolecular controlBody adiposityBiological roleLean massMouse mutantsMeal patterns