Kelly McNagny

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

Current Positions

  • Professor, Medical Genetics, Medicine
  • Biomedical Research Centre

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.

Publications

  1. Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity. 2012 Sep 21;37(3):463-74.
  2. Maltby S, Debruin EJ, Bennett J, Gold MJ, Tunis MC, Jian Z, Marshall JS, McNagny KM. IL-7Rα and L-selectin, but not CD103 or CD34, are required for murine peanut-induced anaphylaxis. Allergy Asthma Clin Immunol. 2012 Aug 31;8(1):15.
  3. Blanchet MR, Gold MJ, McNagny KM. Mouse models to evaluate the function of genes associated with allergic airway disease. Curr Opin Allergy Clin Immunol. 2012 Oct;12(5):467-74.
  4. Hadidi S, Antignano F, Hughes MR, Wang SK, Snyder K, Sammis GM, Kerr WG, McNagny KM, Zaph C. Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. Mucosal Immunol. 2012 Sep;5(5):535-43.
  5. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, Gill N, Blanchet MR, Mohn WW, McNagny KM, Finlay BB. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012 May 1;13(5):440-7.
  6. Cipollone JA, Graves ML, Köbel M, Kalloger SE, Poon T, Gilks CB, McNagny KM, Roskelley CD. The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma. Clin Exp Metastasis. 2012 Mar;29(3):239-52.
  7. Kodippili GC, Spector J, Hale J, Giger K, Hughes MR, McNagny KM, Birkenmeier C, Peters L, Ritchie K, Low PS. Analysis of the mobilities of band 3 populations associated with ankyrin protein and junctional complexes in intact murine erythrocytes. J Biol Chem. 2012 Feb 3;287(6):4129-38.
  8. Alfaro LA, Dick SA, Siegel AL, Anonuevo AS, McNagny KM, Megeney LA, Cornelison DD, Rossi FM. CD34 promotes satellite cell motility and entry into proliferation to facilitate efficient skeletal muscle regeneration. Stem Cells. 2011 Dec;29(12):2030-41.
  9. Anderson NM, Berberovic Z, Berndl E, Bailey ML, Flenniken AM, Osborne LR, Adamson SL, Rossant J, Wang C, Minden MD, McNagny KM, Paulson RF, Barber DL, Stanford WL. Cytopenia induction by 5-fluorouracil identifies thrombopoietic mutants in sensitized ENU mutagenesis screens. Exp Hematol. 2012 Jan;40(1):48-60.
  10. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011 Jul 31;14(9):1142-9.
  11. Blanchet MR, Bennett JL, Gold MJ, Levantini E, Tenen DG, Girard M, Cormier Y, McNagny KM. CD34 is required for dendritic cell trafficking and pathology in murine hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2011 Sep 15;184(6):687-98.
  12. Maltby S, Freeman S, Gold MJ, Baker JH, Minchinton AI, Gold MR, Roskelley CD, McNagny KM. Opposing roles for CD34 in B16 melanoma tumor growth alter early stage vasculature and late stage immune cell infiltration. PLoS One. 2011 Apr 11;6(4):e18160.
  13. Hughes MR, Anderson N, Maltby S, Wong J, Berberovic Z, Birkenmeier CS, Haddon DJ, Garcha K, Flenniken A, Osborne LR, Adamson SL, Rossant J, Peters LL, Minden MD, Paulson RF, Wang C, Barber DL, McNagny KM, Stanford WL. A novel ENU-generated truncation mutation lacking the spectrin-binding and C-terminal regulatory domains of Ank1 models severe hemolytic hereditary spherocytosis. Exp Hematol. 2011 Mar;39(3):305-20, 320.e1-2. Epub 2010 Dec 28.
  14. Kuroda E, Antignano F, Ho VW, Hughes MR, Ruschmann J, Lam V, Kawakami T, Kerr WG, McNagny KM, Sly LM, Krystal G. SHIP represses Th2 skewing by inhibiting IL-4 production from basophils. J Immunol. 2011 Jan 1;186(1):323-32.
  15. Naus S, Blanchet MR, Gossens K, Zaph C, Bartsch J, and McNagny KM, Ziltener HJ. The metalloprotease, ADAM8, is essential for the development of experimental asthma. Am. J. Resp. Crit. Care. Med. 181: 1318-28, 2010.
  16. Grassl G, Faustmann M, Gill N, Zybtnuik L, Merkens H, So L, Rossi F, McNagny KM, Finlay BB*. CD34 mediates intestinal inflammation in Salmonella-infected mice. Cell Micro. (in press), 2010.
  17. Maltby S, Wohlfarth C, Gold M, Zybtnuik L, Hughes MR, McNagny KM. CD34 is required for infiltration of eosinophils into the colon during DSS-induced ulcerative colitis. Am. J. Path. 177:1244-54, 2010. (Faculty of 1000 Choice)

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

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