Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs

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dc.contributor.advisorSenger, Donna L.
dc.contributor.authorRoy Choudhury, Saurav
dc.contributor.committeememberKubes, Paul
dc.contributor.committeememberLiao, Shan
dc.contributor.committeememberMorris, Don G.
dc.contributor.committeememberSchriemer, David C.
dc.contributor.committeememberFerri, Lorenzo Edwin
dc.date2018-06
dc.date.accessioned2018-05-08T17:55:33Z
dc.date.available2018-05-08T17:55:33Z
dc.date.issued2018-04-30
dc.description.abstractLungs and liver are two major sites of neutrophil trafficking and inflammatory disease. Neutrophil recruitment in response to an inflammatory cue is a sequentially coordinated process where adhesion molecules expressed on the endothelium of a given organ mediate different steps in the classical leukocyte recruitment cascade [1]. However, molecules identified as being central in the canonical schema of neutrophil recruitment to different organs (mesentery, skin, and cremaster muscle) are not required in the inflamed pulmonary and hepatic vasculatures [2-8]. Using an unbiased functional screen in vivo, we isolated a peptide-displaying phage that homed to the liver and lungs of mice treated with a bacterial inflammatory stimulus (lipopolysaccharide). Employing intravital microscopy, we found that this phage, or its corresponding displayed-peptide, termed LSALT herein, inhibited the adhesion of neutrophils in the inflamed lungs and liver vasculatures in response to LPS. The corresponding synthetic peptide also reduced the metastatic colonization of melanoma cells to the lungs in human xenograft and immunocompetent mouse models. Using biochemical, genetic and confocal intravital imaging approaches we identified dipeptidase-1 (DPEP1) as the functional target of this peptide and established its role as a physical adhesion receptor for neutrophil and metastatic cancer cell adhesion independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment and cancer metastasis to the lungs and liver, and in models of Acute Respiratory Distress Syndrome (ARDS), prevented septic lung injury and mortality. This study identified DPEP1 as an organ-selective vascular endothelial adhesion receptor for the recruitment of neutrophils and metastatic cancer cells to the lungs and liver and identifies DPEP1 as a novel therapeutic target for systemic inflammatory disorders as well as organ-selective metastatic diseases.en_US
dc.identifier.citationRoy Choudhury, S. (2018). Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/31901en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/31901
dc.identifier.urihttp://hdl.handle.net/1880/106619
dc.language.isoeng
dc.publisher.facultyCumming School of Medicine
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectNeutrophil
dc.subjectmetastatic cancer cell
dc.subjectAdhesion
dc.subject.classificationEducation--Sciencesen_US
dc.subject.classificationImmunologyen_US
dc.subject.classificationEngineering--Biomedicalen_US
dc.titleIdentification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs
dc.typedoctoral thesis
thesis.degree.disciplineMedical Science
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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