UCONN

HEALTH

Photo of Andrei E. Medvedev, Ph.D.

Andrei E. Medvedev, Ph.D.

Associate Professor, Immunology
Academic Office Location:
Department of Immunology
UConn Health
263 Farmington Avenue
Farmington, CT 06030-3710
Phone: (860) 679-7979
Fax: (860) 679-8130
Email: medvedev@uchc.edu
Website(s):

Immunology Graduate Program

Education
DegreeInstitutionMajor
M.Sc.2nd Moscow Medical InstituteBiochemistry
Ph.D.Gabrichevsky Research Institute for Epidemiology and MicrobiologyImmunology

Post-Graduate Training
TrainingInstitutionSpecialty
FellowshipNorwegian Cancer SocietyVisiting Scientist Fellowship
PostdoctoralUniformed Services University of the Health Sciences(USUHS)Department of Microbiology and Immunology

Awards
Name of Award/HonorAwarding Organization
Junior Faculty Travel AwardAmerican Association of Immunology
Junior Faculty Travel AwardAmerican Association of Immunology
Junior Faculty Travel AwardAmerican Association of Immunology
Junior Faculty Travel AwardAmerican Association of Immunology
Junior Faculty Travel AwardAmerican Association of Immunology
Junior Faculty Travel Award, Experimental Biology 2006 Meeting
Junior Faculty Travel Award, Experimental Biology 2002 Meeting
Young Investigator Award5th International Endotoxin Society
Pfizer Prize Award for the best scientific presentationInternational Cytokine Society
Reproductive Scientist AwardRussian Society of Immunologists
Name & DescriptionCategoryRoleTypeScopeStart YearEnd Year
NIH Special Emphasis Panel ZRG1 IMM-N (02) M Advisory CommitteeReviewerExternalNational2012
Telethon grants (the Italian Foundation for Combating Muscular Dystrophies and Other Genetic Diseases, Italy)Advisory CommitteeReviewerExternalInternational2012
Member of the GPILS Award Committee; Danielle Fitzpatrick, Academic Coordinator. GPILS-Epidemiology and Human Genetics Program. Reviewed CVs, letters of recommendations, and personal statements of candidates for outstanding Ph.D. scholar award, outstanding Ph.D. thesis project award, OTANI award, outstanding postdoctoral scholar award, teacher of the year award Advisory CommitteeMemberExternalUniversity2011
Committees on qualifying exams in Immunology and Bacteriology for graduate students (5 students examined) Education CommitteeMemberExternalUniversity2011
Special Emphasis Panel, ZRG1 IMM-N (03), NIH Advisory CommitteeReviewerExternalNational2011
Telethon (the Italian Foundation for Combating Muscular Dystrophies and Other Genetic Diseases, Italy) Advisory CommitteeReviewerExternalInternational2011
Jason Tay, Ph.D. candidate, UMB, thesis advisory committee Advisory Committeecommittee member ExternalUniversity2011
Long Tiha, Ph.D. candidate, UMB, thesis advisory committee Advisory Committeecommittee member ExternalUniversity2011
Allergy, Immunology, and Transplantation Research Committee (AITC 1) for K- and T-series awards, NIAID/NIHAdvisory CommitteeReviewerExternalNational2010
Italian Multiple Sclerosis Society (AISM-FISM) Advisory CommitteeReviewerExternalInternational2010
American Association of Immunologists roaster “High school teachers’ summer research program in immunology” Advisory CommitteeMemberExternalNational20102011
Representative of Department of Microbiology and Immunology to the UMB School of Medicine Council Advisory CommitteeRepresentativeExternalUniversity20092012
Membership Committee, Society for Leukocyte Biology Advisory CommitteeChairExternalNational2009
Melissa Hayes, Ph.D. candidate, UMB, (defended), thesis advisory committee Advisory CommitteeCommittee MemberExternalUniversity20092012
Carlita Philip, Ph.D. candidate, UMB, thesis advisory committee Advisory Committeecommittee member ExternalState20092011
International Endotoxin and Innate Immunity Society Advisory CommitteeScientific Councillor ExternalInternational2008
NIH, Special Emphasis Study Section, NHLBI. Study Sectionreviewer ExternalNational20082009
Victor Ayala, Ph.D. candidate, UMB,(defended), thesis advisory committee Advisory Committeecommittee member ExternalUniversity20072011
Department of Microbiology and Immunology to the UMB Faculty AssemblyEducation CommitteeRepresentativeExternalUniversity20072009
Graduate Program in Life Sciences (GPILS)Advisory CommitteeMemberExternalUniversity2006
Graduate student conference, UMB, Baltimore, MD Advisory CommitteeReviewerExternalUniversity20062009
Innate Immunity Editorial BoardMemberExternalNational2006
American Society for Biochemistry and Molecular Biology Professional/Scientific OrganizationMemberExternalNational2006
Pusha Potnis, Ph.D. candidate, UMB,(defended),thesis advisory committee Advisory Committeecommittee memberExternalUniversity20062010
Intramural Grant Proposals, University of Maryland School of Medicine (UMSOM), Baltimore, MD Advisory CommitteeAd-Hoc Reviewer ExternalUniversity2004
University of Maryland Statewide Health Network (UMSHN) Community Outreach Faculty Resource Directory Community ServiceMemberExternalUniversity2004
Students’ research presentations at annual students’ presentations meetings at UMB Advisory CommitteeReviewerExternalUniversity2004
Scientific Review Committee (SRC), UMSOM Research CommitteeProxyExternalUniversity20042010
Society of Leukocyte Biology Professional/Scientific OrganizationMemberExternalNational2003
American Association of Immunologists Professional/Scientific OrganizationMemberExternalNational2001
PNAS, J. Exp. Med., J. Biol. Chem., J., Immunology, Eur. J. Immunol., Inflammation Res., Obesity, J., Interferon Res., J. Leuk. Biol., Innate Immunity Professional/Scientific JournalAd –hoc reviewerExternalNational1999
International Endotoxin and Innate Immunity Society Professional/Scientific OrganizationMemberExternalInternational1998
Timur Pediashvilli, Ph.D. student, Institute of Human Morphology, Moscow, Russia (defended), thesis advisory committeeAdvisory Committeecommittee memberExternalUniversity19911992

The innate immune system mounts host defense by sensing microbial pathogens and endogenous “danger” molecules by Toll-like receptors (TLRs). TLR-driven signals activate antigen-presenting cells to secrete cytokines and up-regulate co-stimulatory molecules, orchestrating adaptive immune responses. Dr. Medvedev laboratory is focused to determine how distorted control of TLR signaling underlies immune pathologies. The main areas of research focus are:


1) Molecular mechanisms of TLR tolerance. Septic patients surviving “cytokine storm” become immunocompromised and susceptible to secondary infections that often lead to fatal outcomes. Monocytes from such septic patients show predominant expression of TLR-induced anti-inflammatory mediators, similar to TLR-tolerant cells. TLR tolerance is a state of re-programming of TLR signaling during which macrophages or mice exposed to LPS or other TLR agonists show altered responses to subsequent challenge with these agonists. We reported a critical role of tyrosine phosphorylation of TLR4 and the adapter protein Mal in signaling, and their deficiencies in LPS-tolerant monocytes. Our studies revealed impaired activation of IRAK4 and IRAK-1, deficient K63-linked ubiquitination of IRAK-1 and TRAF-6, and increased expression of negative regulators IRAK-M, SHIP-1, and A20 as critical hallmarks of LPS tolerance. Ongoing projects are focused on kinases and phosphatases regulating TLR4 and Mal phosphorylation, the role of E3 ubiquitin ligases Pellinos, micro-RNAs and chromatin modifications in TLR signaling and tolerance. We will use findings obtained in the models of TLR tolerance as a framework for TLR network analyses in patients with sepsis, burns, and trauma.


2) TLR2/4 mutations, bacterial sensing and receptor signaling. Using complementation of cell lines and primary macrophages via transfection, nucleofection and infection with lenti- or retroviruses, the Medvedev laboratory studies the impact of TLR2/4 mutations on binding and phagocytosis of bacteria, signaling, and antimicrobial responses. We will generate humanized knock-in mice expressing mutant TLR2 to determine their susceptibility to infections and immune responses


3) TLR signaling and autoimmunity. Altered TLR signaling plays an important role during systemic inflammatory response syndrome and in autoimmune diseases. We are planning to define relationships between the development of autoimmune states and altered expression and activity of central TLR kinases, IRAK4 and IRAK1, and their regulators in human patients and mouse models of rheumatoid arthritis and lupus. We will design a library of IRAK-4 kinase domain mutants, Mal tyrosine mutants, and truncated versions of these molecules, and will use computer-assisted design to generate small molecule inhibitors. Peptides and small molecules will be tested for their ability to inhibit TLR-inducible pathways in HEK293 transfectants and macrophages, and the most perspective reagents will be tested in vivo in mouse models of sepsis, inflammatory arthritis and systemic lupus erythematous.

Accepting students for Lab Rotations: Summer '17, Fall '17, Spring '18


Project 1: Protein kinases and phosphatases in TLR signaling and tolerance


Project 2: Pellinos and alternatively spliced IRAK species as regulators of TLR signaling


Project 3: TLR2 mutations, signal transduction and macrophage antimicrobial responses


Project 4: Development of Mal and IRAK4 inhibitors as molecular tools for intervention in sepsis and inflammatory disorders

Journal Articles

Book Chapters

  • Analysis of Functional Role of TLR4 Tyrosine Phosphorylation
    Medvedev, A.E, and Piao, W. Toll-Like Receptors 2009 Jan;145-167
  • Toll-like Receptors in the Mammalian Innate Immune System. Series: “Nuclear Acids and Molecular Biology”
    Medvedev, A.E., and Vogel, S.N. Innate Immunity of Plants, Animals and Humans 2008 Jan;135 – 168
  • IRAK-4: A Key Kinase Involved in Toll-Like Receptor Signaling and Resistance to Bacterial Infection
    Medvedev, A.E., Kuhns, D.B., Gallin, J.I., and Vogel, S.N. Toll-like Receptors in Inflammation 2006 Jan;173-192

Reviews

Title or AbstractTypeSponsor/EventDate/YearLocation
Molecular Mechanisms of Endotoxin Tolerance – Insights into Post-translational Modifications of TLRs and Intracellular IntermediatesTalkInflammation Research Group2012University of Maryland, Baltimore
Endotoxin Tolerance Alters LPS-inducible Recruitment of Lyn to TLR4, Protein Tyrosine Phosphatase Activity and Induction of Pellino1TalkFrontiers in Immunology Research Network (FIRN) 2012 Meeting2012Salzburg, Austria
The Asp299Gly Polymorphism Alters TLR4 Signaling by Interfering with Recruitment of Adapter Proteins MyD88 and TRIFTalkAmerican Association of Immunologists (AAI) 2012 Meeting2012Boston, Massachusetts
Regulation of TLR4 Signaling PathwaysTalkOld Dominion University2011Norfolk, Virginia
Reprogramming of TLR4 Signaling in Endotoxin Tolerance: Altered Phosphorylation, Ubiquitination and Induction of Negative RegulatorsTalkMedical University of South Carolina2011Charleston, South Carolina
Regulation of TLR4 Signaling Pathways in Endotoxin ToleranceTalkRosalind Franklin University of Medicine and Science2010Chicago, Illinois
TLR Sensing of Microbial Pathogens and Particulate Matter, Mutations and ToleranceTalkMichigan State University2010East Lansing, Michigan
Molecular Mechanisms of Impaired Sensing of Mycobacteria and Their Components by TLR2 and TLR4 Polymorphic VariantsTalkUniversity of Maryland2010College Park, Maryland
Endotoxin Tolerance Impairs IRAK4 and TAK1 Activation, Polyubiquitination and Signalosome Assembly of IRAK1, TRAF6, IKK-?, and Increases Expression of A20TalkInflammation Research Group2009University of Maryland, Baltimore
Endotoxin Tolerance Reprograms TLR4 Signaling Pathways and Increases Expression of Negative Regulators of TLR SignalingTalkFrontiers in Immunology Research Network (FIRN) 2009 Meeting2009Kona, Hawaii
Endotoxin Tolerance and Re-Programming of TLR4 Signaling PathwaysTalkInflammation Research Group2008University of Maryland, Baltimore
TLR4 Pathway and Endotoxin ToleranceTalkUniversity of Maryland2008College Park, Maryland
Cigarette Smoking Reprograms Toll-like Receptor Responses in Pulmonary MacrophagesPoster6th Annual Forum on Cancer and Other Tobacco-Related Diseases2008Baltimore, Maryland
Endotoxin Tolerance Dysregulates MyD88-Dependent and TRIF-Dependent Signaling Pathways and Increases Expression of Negative Regulators of TLR SignalingTalkExperimental Biology/AAI 2008 Meeting2008San Diego, California
TLR4 Tyrosine Phosphorylation as a Signaling SwitchTalkInflammation Research Group2007University of Maryland, Baltimore
Cigarette Smoking and Innate Immune Responses in Pulmonary MacrophagesTalk5th Annual Scientific Forum on Cancer and Other Tobacco-Related Diseases2007Baltimore, Maryland
Tyrosine phosphorylation of MAL is essential for TLR signaling and is blocked in endotoxin toleranceTalk40th Annual Meeting of the Society for Leukocyte Biology2007Cambridge, Massachusetts
Effect of Cigarette Smoking on Production of Pro- and Anti-Inflammatory Cytokines and Chemokines in Pulmonary MacrophagesTalk4th Annual Scientific Forum on Cancer and Other Tobacco-Related Diseases2006Baltimore, Maryland
IRAK4 Mutations, Tolerance and Decreased Antibacterial Immune ResponseTalkGeorge Washington University2005Washington, D.C.
Molecular Mechanisms of Impaired Antibacterial Sensing: IRAK-4 Mutations and Endotoxin ToleranceTalkNovascreen Inc.2005Columbia, Maryland
The TLR4 Pathway in LPS-Tolerant CellsTalkInternational 2002 Endotoxin Society Meeting2002Washington, DC
Dysregulation of LPS-Induced TLR4-MyD88 Complex Formation and IRAK-1 Activation in Endotoxin-Tolerant CellsTalkExperimental Biology 2002 Meeting2002New Orleans, Louisiana
Limited Role of Ceramide in Lipopolysaccharide-Mediated Mitogen-Activated Protein Kinase Activation, Transcription Factor Induction, and Cytokine ReleaseTalk5th International Endotoxin Society Conference1998Santa Fe, New Mexico
Involvement of the Tumor Necrosis Factor Receptor p75 in Mediating Cytotoxicity and Gene Regulating ActivitiesTalk3rd Annual Conference of International Cytokine Society1995Harrogate, UK