Kelly McNagny

Contact InformationKelly McNagny
2222 Health Sciences Mall
Vancouver, BC, Canada V6T 1Z3
Tel: 1-604-822-7824
Email: kelly@brc.ubc.ca

Current Positions

  • Professor, Medical Genetics, Medicine.
  • Biomedical Research Centre.
  • Michael Smith Foundation for Health Research Senior Scholar.
  • Member, Stem Cell Network of Canada.
  • Associate Director, Allergen NCE Inc., the Allergy, Genes and Environment Network (Canada).

Research Interests

My laboratory is interested in two aspects of hematopoietic stem cell biology: 1) the transcriptional and signaling network that regulates the commitment of multipotent progenitors to a specific lineage, and 2) the surface receptors expressed by HSC that regulate their interacts with their microenvironment.

Transcriptional and signaling networks
We are focusing on the regulatory mechanisms that govern mast cell and eosinophil production. These are relatively rare cells that are responsible for most of the pathology in chronic allergy and asthma and therefore may represent good targets for clinical intervention. We are using a number of transgenic mouse models to identify the factors that govern mast cell and eosinophil formation, homing and function and to perturb these processes during normal development.

Surface molecules expressed by HSC
We have focused predominantly on CD34-type proteins. CD34 is a cell surface sialomucin and the most widely used marker of hematopoietic stem cells and vascular endothelia. Recently we identified two novel receptors, Podocalyxin (also called MEP21, gp135, Thrombomucin and PCLP1) and Endoglycan that are also expressed by hematopoietic stem/progenitor cells and vasculature. We have shown that, together with CD34, these additional molecules comprise a gene family and that all three are probably derived from a common ancestral gene. Surprisingly, despite the extensive use of CD34 as a stem cell marker, virtually nothing is known of its function and it has alternatively be touted as a: 1) blocker of HSC differentiation 2) enhancer of HSC proliferation 3) bone marrow homing receptor 4) pro-adhesive receptor 5) anti-adhesive receptor.

Targeted deletion of the CD34 gene in mice has only fueled the debate concerning its function since these mice exhibit extremely subtle perturbations in normal hematopoietic function that could be used to support each of the above hypotheses. The discovery of two novel members of this gene family with overlapping expression patterns, has allowed us to: (1) re-evaluate these results in light of the potential for functional compensation and, (2) to generate compound mutant mice to test the true function of these receptors. In aggregate, these studies have allowed us to prove that the CD34 family of proteins function predominantly as anti-adhesion molecules, or “molecular Teflon”. Thus, they enhance the mobility and invasiveness of hematopoietic cells and on non-hematopoietic cells, they are able to disrupt cell-cell junctional complexes between neighboring adherent cells (vascular endothelia or podocytes in the kidney, for example). This is not a constitutive function, but is tightly regulated by a set of proteins that bind to the cytoplasmic tail of CD34-type proteins and regulate their sub-cellular localization and proximity to adhesion molecules. Preliminary data suggest that loss of CD34-type proteins leads to defects in hematopoietic function by preventing the HSC from entering the appropriate micro-environments (due to excessive adhesion). Similarly, we have shown that loss of these proteins can lead to dysregulation of blood pressure, presumably due to increased cell-cell adhesion and decreased vascular permeability. Finally, we have shown that these same “anti-adhesion” molecules are upregulated in an aggressive subset of epithelial tumors and lead to increased invasiveness and loss of cell polarity. They may, thus, prove to be excellent prognostic indicators of poor outcome tumors and provide a means of identifying these cancers early for aggressive therapy.

Selected Publications

  1. Chow LN, Schreiner P, Ng BY, Lo B, Hughes MR, Scott RW, Gusti V, Lecour S, Simonson E, Manisali I, Barta I, McNagny KM, Crawford J, Webb M, Underhill TM. Impact of a CXCL12/CXCR4 antagonist in bleomycin (BLM) induced pulmonary fibrosis and carbon tetrachloride (CCl4) induced hepatic fibrosis in mice. PLoS One 11: e0151765, 2016.
  2. Hosseini A, Hirota JA, Hackett TL, McNagny KM, Wilson SJ, Carlsten C. Morphometric analysis of inflammation in bronchial biopsies following exposure to inhaled diesel exhaust and allergen challenge in atopic subjects. Part Fibre Toxicol 13: 2, 2016.
  3. Gold MJ, Antignano F, Hughes MR, Zaph C, McNagny KM. Dendritic-cell expression of SHIP-1 regulates Th2 immunity to helminth infection in mice. Eur J Immunol 46: 122-130, 2016.
  4. Graves ML, Cipollone JA, Austin P, Bell EM, Nielsen JS, Gilks CB, McNagny, KM, Roskelley CD. The cell surface mucin podocalyxin regulates collective breast tumor budding. Breast Cancer Res 18: 11, 2016.
  5. Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6: 8715, 2015.
  6. Gold MJ, Hiebert PR, Park HY, Stefanowicz D, Le A, Starkey MR, Deane A, Brown AC, Liu G, Horvat JC, Ibrahim ZA, Sukkar MB, Hansbro PM, Carlsten C, VanEeden S, Sin DD, McNagny KM, Knight DA, Hirota JA. Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization. Mucosal Immunol 9: 809-820, 2016.
  7. Arrieta M-C, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, Kuzeljevic B, Gold MJ, Britton HM, Lefebvre DL, Subbarao P, Mandhane P, Becker A, McNagny KM, Sears MR Kollmann T, the CHILD Study Investigators, Mohn WW, Turvey SE, Finlay BB. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 7: 307ra152, 2015.
  8. Bernatchez E, Gold MJ, Langlois A, Lemay A-M, Brassard J, Flamand N, Marsolais D, McNagny KM, Blanchet M-R. Pulmonary CD103 expression regulates airway inflammation in asthma. Am J Physiol Lung Cell Mol Physiol 308: L816-826, 2015.
  9. Hui CCK, McNagny KM, Denburg JA, Siracusa MC. In situ hematopoiesis: a regulator of Th2 cytokine-mediated immunity and inflammation at mucosal surfaces. Mucosal Immunol 8: 701-711, 2015.
  10. Snyder KA, Hughes MR, Hedberg B, Brandon J, Hernaez DC, Bergqvist P, Cruz F, Po K, Graves ML, Turvey ME, Nielsen JS, Wilkins JA, McColl SR, Babcook JS, Roskelley CD, McNagny KM. Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy. Breast Cancer Res 17:46, 2015.
  11. Gold MJ, Hughes MR, Antignano F, Hirota JA, Zaph C, McNagny KM. Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain-containing inositol 5- phosphatase (SHIP-1). J Allergy Clin Immunol 136: 725-736, 2015.
  12. Zhang P, Riazy M, Gold MJ, McNagny KM, Proud C, Duronio V. Impairing eukaryotic elongation factor 2 kinase activity decreases atherosclerotic plaque formation. Can J Cardiol 30: 1684-1688, 2014.
  13. Haddon DJ, Jarrell JA, Hughes MR, Snyder K, McNagny KM, Kattah MG, Utz PJ. Measurement of mast cell surface molecules by high-throughput immunophenotyping using transcription (HIT). Methods Mol Biol 1220: 381-400, 2015.
  14. DeBruin EJ, Gold M, Lo BC, Snyder K, Cait A, Lasic N, Lopez M, McNagny KM, Hughes MR. Mast cells in human health and disease. Methods Mol Biol 1220: 93-119, 2015.
  15. Hughes MR, McNagny KM. Preface: Mast Cells. Methods Mol Biol 1220: vii-viii, 2015.
  16. DeBruin EJ, Hughes MR, Sina C, Lu A, Cait J, Jian Z, Lopez M, Lo B, Abraham T, KM McNagny. Podocalyxin regulates lung vascular permeability by altering endothelial cell adhesion PLoS One 9: e108881, 2014.
  17. Hirota JA, Gold MJ, Hiebert PR, Parkinson LG, Wee T, Smith D, Hansbro PM, Carlsten C, VanEeden S, Sin DD, McNagny KM, Knight DA. The nucleotide-binding domain, leucine-rich repeat protein 3 inflammasome/IL-1 receptor I axis mediates innate, but not adaptive, immune responses after exposure to particulate matter under 10 μm. Am J Respir Cell Mol Biol 52: 96-105, 2015.
  18. Russell SL, Gold MJ, Reynolds L, Willing BP, Dimitriu P, Thorson L, Redpath SA, Perona-Wright G, Blanchet MR, Mohn WW, Finlay BB*, McNagny KM*. Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases. J Allergy Clin Immunol 135: 100- 109, 2015. *Co-corresponding authors.
  19. Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet M-R, Zaph C, Takei F, McNagny KM. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J Allergy Clin Immunol 133: 1142-1148, 2014.
  20. Carlsten C, Brauer M, Brinkman F, Brook J, Daley D, McNagny K, Pui M, Royce D, Takaro T, Denburg J. Genes, the environment and personalized medicine: We need to harness both environmental and genetic data to maximize personal and population health. EMBO Rep 15: 736- 739, 2014. Authors listed alphabetically with exception of first and last.
  21. Halim TYF, Steer CA, Mathä L, Gold MJ, Martinez-Gonzales I, McNagny KM, McKenzie AN, Takei F. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40: 425-435, 2014.
  22. Antignano F, Burrows K, Hughes MR, Han JM, Kron KJ, Penrod NM, Oudhoff MJ, Wang SK, Min PH, Gold MJ, Chenery AL, Braam MJ, Fung TC, Rossi FM, McNagny KM, Arrowsmith CH, Lupien M, Levings MK, Zaph C. Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. J Clin Invest 124: 1945-1955, 2014.
  23. Blanchet M-R, Gold M, McNagny KM. Mutant mice and animal models of allergic airway disease. Methods Mol Biol 1178: 295-308, 2014.
  24. Aloyouni SY, Segeritz C-P, Sherrid AM, Gold MJ, Loeffler DIM, Blanchet M-R, Cai B, Hirota J, McNagny KM*, Kollmann TR*. Perinatal immunization with vaccine-grade Listeria monocytogenesprovides protection against murine Th2 airway inflammation. Allergy Asthma Immunol Res 6: 341- 349, 2014. *Co-Corresponding authors.
  25. Anderson NM, Javadi M, Berndl E, Berberovic Z, Bailey ML, Huang K, Flenniken AM, Osborne LR, Adamson SL, Rossant J, Carter-Su C, Wang C, McNagny K, Paulson RF, Minden MD, Stanford WL, Barber DL. Enu mutagenesis identifies a novel platelet phenotype in a loss-of-function Jak2 allele. PLoS One 8: e75472, 2013.
  26. Sham HP, Yu EY, Gulen MF, Bhinder G, Stahl M, Chan JM, Brewster L, Morampudi V, Gibson DL, Hughes MR, McNagny KM, Li X, Vallance BA. SIGIRR, a negative regulator of TLR/IL-1R signalling promotes Microbiota dependent resistance to colonization by enteric bacterial pathogens. PLoS Pathog 9: e1003539, 2013.
  27. Scherberich A, Di Maggio ND, McNagny KM. A familiar stranger: CD34 expression and putative functions in SVF cells of adipose tissue. World J Stem Cells 5: 1-8, 2013.
  28. Hirota J, Hiebert PR, Gold M, Wu D, Graydon C, Ask K, McNagny KM, Granville DJ, Knight D. Granzyme B deficiency exacerbates lung inflammation in mice following acute lung injury. Am J Respir Cell Mol Biol 49: 453-462, 2013.
  29. Mullaly SC, Oudhoff MJ, Min PH, Burrows K, Antignano F, Rattray DG, Chenery A, McNagny KM, Ziltener HJ, Zaph C. Requirement for core 2 O-glycans for optimal resistance to helminth infection. PLoS One 8:e60124, 2013.
  30. Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM*, Finlay BB*. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4: 158-164, 2013. *Co-corresponding authors.

Education

  • Postdoctorate (Molecular Biology) European Molecular Biology Lab, Germany, 1996.
  • Ph.D. (Immunology) University of Alabama at Birmingham, USA, 1990.
  • B. Sc. (Biology and Biotechnology Fermentation Biology), Worcester Polytechnic Institute, USA, 1984.