UCONN

HEALTH

Photo of Linda Hillstrom Shapiro, Ph.D.

Linda Hillstrom Shapiro, Ph.D.

Professor, Department of Cell Biology
Director, Center for Vascular Biology
Academic Office Location:
Cell Biology
UConn Health
263 Farmington Avenue
Farmington, CT 06030-3501
Phone: 860-679-4373
Fax: 860-679-1201
Email: lshapiro@neuron.uchc.edu
Website(s):

Cell Biology Graduate Program

Education
DegreeInstitutionMajor
B.S.University of Notre DameMicrobiology
M.S.University of MichiganMicrobiology and Immunology
Ph.D.University of MichiganMicrobiology and Immunology

Post-Graduate Training
TrainingInstitutionSpecialty
PostdoctoralNational Institute of Allergy and Infectious DiseasesImmunology
PostdoctoralUniversity of MichiganHuman Genetics

Awards
Name of Award/HonorAwarding Organization
National Research Service Award, 1986-1988National Institutes of Health
Thurnau Postdoctoral Fellowship 1985-1986University of Michigan
Damon Runyon-Walter Winchell Cancer Fund Fellowship 1984-1985 Damon Runyon Cancer Research Foundation
Name & DescriptionCategoryRoleTypeScopeStart YearEnd Year
Education Committee, North American Vascular Biology AssociationEducation CommitteeMemberExternalInternational2016
Dean's Council of Research AdvisorsAdvisory CommitteememberUConn HealthUniversity2016
PPG review Dr. Joseph Wiztzum PI, UCSDOtherMemberExternalNational20132013
Ad Hoc Reviewer AICS NIHStudy SectionmemberExternalNational2013
Search Committee- Associate Dean for Faculty AffairsAdvisory CommitteememberUConn HealthUniversity20132013
PPG review Dr. Catherine Hedrick PI, LaJolla Institute for ImmunologyOtherMemberExternalNational20122012
Research CouncilResearch CommitteememberUConn HealthUniversity2012
Basic Science Leadership CouncilAdvisory CommitteememberUConn HealthUniversity2012
L Building Renovation CommitteeAdvisory CommitteememberUConn HealthLocal2012
Search Committee- Chairman of PediatricsAdvisory CommitteememberUConn HealthUniversity20122012
CCESCEducation CommitteeMemberUConn HealthUniversity2011
GWIMS UCHCAdvisory CommitteeMemberUConn HealthNational2011
Student Evaluation and Appeal Review Committee Advisory CommitteeMemberUConn HealthUniversity2011
UCHC Research Council Advisory CommitteeMemberUConn HealthUniversity2011
Graduate Women in Medicine and Science Steering Committee, UCHC Advisory CommitteeMemberUConn HealthUniversity2011
Course and Curriculum Evaluation Subcommittee Advisory CommitteeMemberUConn HealthUniversity2011
Ad Hoc PPG ReviewStudy SectionReviewerExternalNational20102011
Wellcome Trust Senior Fellowship AwardAdvisory CommitteeReviewerExternalInternational20102010
SEARCAdvisory CommitteememberUConn HealthUniversity2010
Cell Biology Graduate Program Advisory CommitteeAssistant DirectorUConn HealthUniversity20092010
American Association of ImmunologistsProfessional/Scientific OrganizationmemberExternalNational2008
Journal of Biological Chemistry Editorial BoardMemberExternalNational20072012
Atherosclerosis and Inflammation in the Cardiovascular System study section, (AICS) NIH Study SectionMemberExternalNational20062011
Erythrocyte & Leukocyte Biology (ELB) Study Section, Special Emphasis PanelStudy SectionMemberExternalNational20052005
Hematopoiesis study section NCI; Atherosclerosis and Inflammation in the Cardiovascular System study section, NHLBI Study SectionAd Hoc ReviewerExternalNational20042005
Atherosclerosis and Inflammation in the Cardiovascular System (AICS) Study Section, National Institutes of HealthStudy SectionAd Hoc ReviewerExternalNational20042006
Hematopoiesis Study Section, National Institutes of HealthStudy SectionAd Hoc ReviewerExternalNational20042006
Association for International Cancer ResearchProfessional/Scientific OrganizationAd Hoc ReviewerExternalInternational20042004
Leukemia, Immunology, and Blood Cell Development Peer Review Committee, American Cancer SocietyAdvisory CommitteeMemberExternalNational20032006
Leukemia, Immunology, and Blood Cell Development Study Section, American Cancer Society Study SectionMemberExternalNational20022006
MD/PhD Steering CommitteeEducation CommitteeMemberUniversity2002
Dutch Cancer Society Professional/Scientific OrganizationAd Hoc ReviewerExternalInternational20022002
Transcriptional Regulation of Myeloid Hematopoiesis, American Society for Hematology Annual MeetingWorkshop/ConferenceSession ChairExternalNational20022002
Leukemia, Immunology, and Blood Cell Development Peer Review Committee, American Cancer SocietyAdvisory CommitteeAc Hoc ReviewerExternalNational20022002
American Society for Hematology Annual Meeting, Transcriptional Regulation of HematopoiesisAdvisory CommitteeAbstract ReviewerExternalNational20022002
Graduate Program in Cell Biology, University of Connecticut Health CenterAdvisory CommitteeDirectorUConn HealthUniversity20012009
Graduate School Admissions CommitteeAdvisory CommitteeMemberUConn HealthUniversity2001
Graduate Program Committee Advisory CommitteeMemberUConn HealthUniversity20012009
American Society for Hematology Annual Meeting, Transcriptional Regulation of HematopoiesisWorkshop/ConferenceAbstract ReviewerExternalNational20002000
NCI Program Project, P.I: .Dr. Joseph S. Lipsick, "Intra-and Extracellular Signaling in Oncogenesis.", Stanford UniversityAdvisory CommitteeReviewerExternalUniversity20002000
NIDDK Program Project, Massachusetts General HospitalAdvisory CommitteeReviewerExternalLocal19991999
Wellcome Trust Senior Fellowship AwardAdvisory CommitteeReviewerExternalInternational19992001
Blood Professional/Scientific JournalReviewerExternalNational
Molecular and Cellular BiologyProfessional/Scientific JournalReviewerExternalNational
LeukemiaProfessional/Scientific JournalReviewerExternalNational
Experimental Cell ResearchProfessional/Scientific JournalReviewerExternalNational
OncologyProfessional/Scientific JournalReviewerExternalNational
Cancer ResearchProfessional/Scientific JournalReviewerExternalNational
Cell Growth and DifferentiationProfessional/Scientific JournalReviewerExternalNational
Journal of Cellular BiochemistryProfessional/Scientific JournalReviewerExternalNational
Journal of the National Cancer InstituteProfessional/Scientific JournalReviewerExternalNational
OncogeneProfessional/Scientific JournalReviewerExternalNational
ImmunologyProfessional/Scientific JournalReviewerExternalNational
Clinical and Experimental ImmunologyProfessional/Scientific JournalReviewerExternalNational
GeneProfessional/Scientific JournalReviewerExternalNational
BiotechniquesProfessional/Scientific JournalReviewerExternalNational
International Journal of CancerProfessional/Scientific JournalReviewerExternalInternational
Atherosclerosis, Thrombosis, and Vascular BiologyProfessional/Scientific JournalReviewerExternalNational
Biochemical JournalProfessional/Scientific JournalReviewerExternalNational
National Science FoundationProfessional/Scientific OrganizationReviewerExternalNational
Veterans Administration Merit AwardAdvisory CommitteeReviewerExternalNational

Research in the Shapiro laboratory concentrates on understanding the regulation and function of cell surface peptidases in the angiogenic endothelium of tumors, vessels at sites of inflammation and in cardiovascular disease. Numerous cell surface peptidases are strikingly upregulated on angiogenic endothelial cells leading to the hypothesis that these may functionally cooperate in enzymatic cascades to regulate angiogenesis and endothelial cell function. While the angiogenic significance of proteases that cleave large proteins (such as the matrix metalloproteases) is well documented, increasing evidence supports a role for peptidases (metAP2, CD13, APA, PSMA) as angiogenic regulators as well. The fact that these enzymes metabolize small peptide substrates suggests that small molecule regulators of angiogenesis exist which have yet to be identified and whose mechanisms are unknown. Indeed, we have shown that individually, two peptidases, CD13 and PSMA are potent regulators of angiogenesis and our investigation of their regulatory mechanisms and their possible interaction is the current focus of the laboratory.We have shown that inhibition of CD13/APN blocks endothelial morphogenesis and invasion and we continue to examine the molecular mechanisms responsible for its angiogenic regulatory capabilities, particularly its role in invasion. Recent studies from our lab suggest that CD13 regulates signal transduction pathways leading to invasion by participating in plasma membrane organization via its interaction with membrane cholesterol. Further investigations have indicated that CD13 also functions as an adhesion molecule where it mediates inflammatory cell interactions as well as endothelial/extracellular matrix interactions in a signal transduction dependent manner which has strong implications for regulation of inflammatory leukocyte trafficking and angiogenic cell invasion. Furthermore, CD13 is expressed on adult pluripotent stem cells and may play a role in stem cell trafficking as well. Finally, high levels of CD13 are found in the serum of patients with certain types of cancers and inflammatory diseases and we are currently investigating the mechanisms regulating its release from the cell surface and CD13’s utility as a serum biomarker of chemoprevention in breast cancer and myocardial infarction. We have recently produced a conditional CD13 knockout mouse and are actively characterizing CD13’s contribution to various physiologic and pathologic processes by specifically inactivating the gene in specific tissues.Our investigation into the function of a second cell surface peptidase, PSMA has shown that this peptidase also regulates cell signaling, albeit by an apparently different mechanism. Investigation of PSMA’s regulation of endothelial cell adhesion led to the very interesting discovery that PSMA is a component of a complex regulatory loop that controls integrin signaling and PAK1 activation. Invasion studies with PSMA-null cells showed that PSMA regulates cell invasion by controlling signaling from beta1 integrins to focal adhesion kinase (FAK) and PAK1. We showed that PSMA interacts with the actin-binding protein filamin A, and disruption of this interaction decreases the peptidase activity of PMSA and phosphorylation of PAK1 in cultured cells. The interaction of PMSA with the cytoskeleton via filamin A allows a feedback signal from integrin beta1 and PAK that holds PMSA activity in check. Inhibition of PAK by expression of a peptide corresponding to its autoinhibitory domain enhanced the association of PMSA with filamin A, thus increasing its peptidase activity. These studies suggest an extracellular matrix derived, small molecule PSMA substrate that superactivates beta1 integrins, thus regulating angiogenesis and cell invasion. The manuscript describing this work was recently featured as a ‘highlight of the recent literature’ by the editors of Science.Investigation into the regulation and function of these molecules will increase our understanding of molecular mechanisms controlling blood vessel formation in a variety of diseases such as cancer, heart disease, inflammatory disorders, diabetic retinopathy, and arthritis.Future Directions We will extend the laboratory’s observations on the roles of cell surface peptidases in various pathologic states. We have conditional CD13 knockout animals and complete PSMA knockouts, so both in vitro and in vivo studies are feasible. For CD13, experiments will be directed toward its role as an adhesion molecule on endothelial cells and monocytes and its potential regulation of inflammation, inflammatory diseases and cancer. Specific areas of research will elucidate its interacting adhesion partners, its place in the established paradigm of leukocyte trafficking, characterization of the signal transduction cascades induced by CD13 and investigation of its internalization and re-expression on the membrane. In addition, studies will continue on the mechanism of CD13 shedding and the function of soluble CD13 in inflammation and stem cell trafficking. Studies regarding PSMA will focus on its role as an angiogenic regulator and its control of cell invasion via integrin signaling. Specifically we will concentrate on identifying its angiogenic/integrin activating peptide substrate, the concept of regulation of angiogenesis by small extracellular matrix derived-peptide fragments and the role of PSMA in prostate tumorigenesis and invasion.

Accepting students for Lab Rotations:  Spring '18


Lab Rotation Projects CD13 --Investigation of signal transduction pathways induced by CD13 ligation in endothelial cells that lead to increased cell adhesion and their roles in inflammatory leukocyte trafficking. --Structure/function analysis of CD13’s signaling and adhesion functions using chimeric mouse/human molecules. Characterization of the role of CD13 in inflammation in response to bacterial infection. --Characterization of CD13’s participation in inflammatory disease models. --Investigation of CD13’s contribution to leukocyte trafficking in inflammation. --Molecular dissection of the reorganization of the monocyte cytoskeleton following CD13 ligation. --Assess the role of CD13 as an adhesion molecule of endothelial junctions. CD13 relocates to the cell-cell junctions as cells become confluent, suggesting it participates in junction formation and endothelial permeability. --Characterization of the role of upregulated CD13 expression following myocardial ischemia in mouse models of myocardial infarction (in collaboration with Bruce Liang, Calhoun Center for Cardiology). --Investigation into serum CD13 as a biomarker in inflammatory and cardiovascular disease.PSMA --Structure/function analysis of PSMA’s regulation of beta 1 integrin signaling. --Assessing PSMA as an endothelial adhesion molecule. --Assessing endothelial PSMA in the angiogenesis during wound healing. --Investigating the role of PSMA in prostate cancer metastasis. PSMA regulates prostate cancer cell invasion suggesting it may regulate escape from the primary tumor and access to metastatic sites. --Investigation into how PSMA expression on tumor blood vessels affects endothelial/basal lamina interactions and vessel permeability.

Journal Articles

Book Chapters

  • CD13/aminopeptidase N in Tumor Growth & Angiogenesis
    N Petrovic, W Schacke, LH Shapiro Aminopeptidases in Biology and Disease 2004 Jan;179-200
  • CD13/APN as a Target for Inhibiting Tumor Angiogenesis: A Molecular Basis for the Differential Expression of CD13/APN in Vascular Endothelium
    SV Bhagwat, Y Okamoto, LH Shapiro Ectopeptidases 2002 Jan;123-140
  • Report of the CD13 (aminopeptidase N) cluster workshop
    Ashmun RA, Holmes KV, Shapiro LH, Favaloro EJ, Razak K, deCrom RPG, Howard CJ, Look AT Leukocyte Typing V 1995 Jan;771-775
  • Report of the CD13 (aminopeptidase N) cluster workshop
    Look AT, Ashmun RA, Shapiro LH, O'Connell PJ, Gerkis V, d'Apice AJ, Sagawa K, Peiper SC Leukocyte Typing IV 1989 Jan;784-787
  • Complementing Ir-genes located in the I-A subregion and between the S and D regions are required for the response to TNP-Ficoll
    Hillstrom LM, Niederhuber JE Ir-Genes: Past, present and future 1983 Jan;109

Other

Reviews

Title or AbstractTypeSponsor/EventDate/YearLocation
CD13 Regulation of Endocytic Integrin RecyclingPosterGordon Conference2016New Hampshire
CD13 Regulation of Dendritic Cell EndocytosisPosterKeystone Symposia2016Killarney, Ireland
CD13 as a Vascular RegulatorTalkUniversity of Iowa2016Iowa City, IA
CD13 as a Vascular RegulatorTalkMedical College of Georgia2016Augusta, GA
CD13 Regulation of Innate ImmunityTalkAmerican Association of Immunology2015New Orleans, LA
CD13 is a Novel Regulator of TLR4 Endocytosis in Dendritic CellsPosterKeystone Symposia2013Keystone, CO
Modulation of CD13 expression may enhance stem cell engraftment for tissue and organ repairPosterSTEMConn2013New Haven, CT
Matrix and Biomechanical SignalsLectureGordon Research Conference on Vascular Cell Biology2013Ventura, California
CD13 Normalizes Vasculature in Solid Tumors and Regulates Adherens JunctionsPosterUniversity of Connecticut Health Center Graduate Student Research Day2013Farmington, Connecticut
Department of Microbiology and Immunology Seminar SeriesTalkNortwestern University2013Chicago, IL
Pediatric Research Seminar SeriesTalkConnecticut Children's Medical Center2013Farmington, CT
CD13 regulates immune cell trafficking to solid tumorsTalkAmerican Association of Immunologists National Research Conference2012Boston, MA
CD13 phosphorylation and cytoskeletal anchors in Monocyte adhesionPosterNorth American Vascular Biology Organization2012Hyannis, MA
CD13 regulates dendritic cell cross-presentation and t cell responses by inhibiting receptor-mediated antigen uptake TalkAmerican Association of Immunologists Annual Meeting2012Boston, MA
Modulation of CD13 expression may enhance stem cell engraftment for tissue and organ repairPosterNew York Stem Cell Foundation2012New York, NY
CD13 is involved in immune cell trafficking in inflammation and solid tumorsPosterNorth American Vascular Biology Organization2011Hyannis, MA
Trafficking and functional roles of myeloid cells lacking CD13 in inflammatory diseasesPosterGordon Conference2011Newport, RI
CD13 Regulates Mesenchymal Stem Cell FunctionPosterNorth American Vascular Biology Organization (NAVBO) Research Conference2011
Special Seminar TalkInstitute of Medical Biology/Biochemistry, Ernst-Moritz-Arndt University2011Greifswald, Germany
Kentucky Pediatric Research Institute SeminarTalkUniversity of Kentucky2008Lexington, KY
Vascular Biology Seminar Series TalkYale University Medical School2005New Haven, CT
Keynote Speaker Talk4th St. Gerlach Vascular Biology Congress2002St. Gerlach, Netherlands
Vascular Biology Seminar SeriesTalkDartmouth Medical School2002Hanover, NH
Center for Vascular Biology Seminar SeriesTalkUniversity of Connecticut Medical School2001Farmington, CT
Conference on Cell Surface Peptidases TalkDanish Society for Biochemistry and Molecular Biology 2001Copenhagen, Denmark