Mark Sleeman, PhD
About
Biography
Dr Sleeman has a combined background in neurobiology, endocrinology and biochemistry and he has published in journals such PNAS, Cell Metabolism and Nature Medicine, Genetics and Neuroscience. He is a leader within the field of metabolic research and his work has often challenged established theories in insulin signaling and diabetes (role of ChREBP, SHIP2 and Trb3) and at other times been seminal in expanding fields of research, such as for gut peptide ghrelin. Common to all studies is the combined use of mouse and human genomic approaches, gene expression analysis coupled with detailed physiological studies to understand primary mechanism of action. His leadership qualities are evident by the ability to simultaneously lead a discover research and therapeutic development team in a world-class biotechnology company.
Appointments
Comparative Medicine
Professor AdjunctPrimary
Other Departments & Organizations
Education & Training
- PhD
- Monash University (1989)
Research
Overview
Dr. Sleeman is the Head of Metabolic Research at Regeneron Pharmaceuticals in Tarrytown, New York. For the past two decades he has been interested in the interplay between insulin resistance and obesity, and more specifically the molecular mechanisms behind the regulation food intake and body weight. Recently, his research has focused on the role that gut hormones such as ghrelin and PYY play in signaling to a number of brain regions to modulate metabolic events. To that end he and his colleagues have generated a large number of genetically modified animals to study these phenotypes. Ultimately, his work may clarify the complex relationships on the role that circulating hormones play in regulation of short and long term metabolic events such as bone and mineral metabolism and food intake&body weight control.
Mark Sleeman was a recipient of a Juveniles Diabetes and Ruth Kirschstein Endocrine Fellowship at the University of Massachusetts in the laboratory of Dr Michael P. Czech where he studied mechanisms insulin-resistance/signaling. Dr Sleeman received his Ph.D. from Monash University, Australia, where he specialized in neurobiology and has published numerous papers in Type 2 Diabetes and Obesity in journals such as Nature Medicine, Nature Genetics, PNAS, Journal of Biological Chemistry and Diabetes and is a member of numerous professional societies in US.
ORCID
0000-0002-3329-0919
Research at a Glance
Yale Co-Authors
Publications Timeline
Tamas Horvath, DVM, PhD
Tormod Rogne, MD, PhD
Publications
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 ResearchConceptsPlasma 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsAssociation 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 ResearchAltmetricConceptsWnt 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsLeptin 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 ResearchCitationsAltmetricConceptsProprotein 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
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