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
Connecticut Academy of Science and Engineering MemberCASE
GWIMS Mentoring AwardGWIMS
Outstanding Scientist AwardGWIMS
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
Reviewer- Pharmacy Interdisciplinary GrantsStudy SectionmemberUConn-StorrsState20202020
Reviewer- Keck Research Grant ProgramStudy SectionmemberUConn-StorrsNational20202020
Public Issues CouncilAdvisory CommitteememberUConn HealthRegional2019
Department of Immunology ReviewAdvisory CommitteememberUConn HealthLocal20192019
Vascular Biology Publications AlertAdvisory CommitteeEditorExternalInternational2019
Search Committee, CCAM DirectorAdvisory CommitteememberUConn HealthLocal2019
Council Member- North American Vascular Biology Organization (NAVBO)Advisory CommitteememberExternalInternational2019
Co-chair, Block Symposium “Leukocyte adhesion and migration" 2018 American Association of Immunology annual meeting, Austin Texas May 4-8, 2018.Professional/Scientific Organizationco-chairExternalNational20182018
Senior Appointments and Promotions CommitteeAdvisory CommitteeSecondary ReviewerUConn HealthUniversity2017
NIDDK Review of O'Brien Kidney Research GrantsStudy SectionmemberExternalNational20172017
VCMB Study SectionStudy Sectionad-hoc memberExternalNational20172017
Search Committee, Chair of NeuroscienceAdvisory CommitteememberUConn HealthNational20172017
Education Committee, North American Vascular Biology AssociationEducation CommitteeMemberExternalInternational20162019
Research CouncilResearch CommitteememberUConn HealthUniversity2012
CCESCEducation CommitteeMemberUConn HealthUniversity2011
Graduate Women in Medicine and Science Steering Committee, UCHC Advisory CommitteeMemberUConn HealthUniversity2011
Ad Hoc PPG ReviewStudy SectionReviewerExternalNational20102011
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
Leukemia, Immunology, and Blood Cell Development Peer Review Committee, American Cancer SocietyAdvisory CommitteeMemberExternalNational20032006
Graduate School Admissions CommitteeAdvisory CommitteeMemberUConn HealthUniversity2001
Graduate Program Committee Advisory CommitteeMemberUConn HealthUniversity20012009
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
Stem Cell Research and TherapyProfessional/Scientific JournalreviewerNational

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.

Not accepting lab rotation students at this time 

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

Letters

Other

Reviews

Title or AbstractTypeSponsor/EventDate/YearLocation
Seventeenth Annual New England Science Symposium CD13 Promotes Tunneling Nanotube Formation and Cell-cell Communication in Human Endothelial Cells and Mouse Primary Macrophages Brian Aguilera, Linda Shapiro and Mallika GhoshPosterNew England Science Symposium2018Harvard Medical School, Boston, MA
Renal CD13/aminopeptidase N: Brush Border Peptidase, Regulator of Albumin Uptake and Potential Urinary BiomarkerTalkNew York Medical College2017Valhalla, NY
CD13 is a Regulator of Cell-ECM AdhesionTalkUniversity of Washington School of Public Health2017Seattle, WA
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