McMaster University

McMaster University

Brad Doble

Brad Doble

Scientist

McMaster Stem Cell and Cancer Research Institute (SCC-RI)

Assistant Professor, Department of Biochemistry and Biomedical Sciences

Dr. Doble’s research program is focused on understanding the signaling mechanisms that maintain embryonic stem cells in a pluripotent self-renewing state versus those that promote their differentiation into specialized cell types. He is particularly interested in understanding how signals are relayed through cells via changes in the phosphorylation status of signaling molecules. Enzymes called kinases are responsible for phosphorylating proteins, often dramatically changing the function of the protein targets.

Of particular interest to the Doble lab is the multifunctional protein kinase, glycogen synthase kinase-3 (GSK-3). GSK-3 controls the function of many cellular processes, and is strongly linked to the regulation embryonic stem cell self-renewal and differentiation. GSK-3 is a central regulator of the developmentally important Wnt/b-catenin signaling pathway, which likely plays a large part in GSK-3’s regulation of stem cells.

The current projects in the Doble lab are focused on understanding the mechanisms through which GSK-3 and Wnt/b-catenin signaling regulate embryonic and adult stem cell properties. Understanding the unique properties of stem cells is important if they are to be safely used as sources of differentiated cells for regenerative medicine purposes. As well, insights into the mechanisms regulating stem cell self-renewal has the potential to be applied to cancer therapies, since the same self-renewal pathways utilized by stem cells are “hijacked” by cancer cells.

Education

2001 Ph.D., Physiology, University of Manitoba

Honours and Awards

Year Description
2010 - 2013 CIHR Operating Grant: The role of GSK-3 in stem cell self-renewal and differentiation
2007 - 2012 Tier II Canada Research Chair in Stem Cell Signaling
2001 - 2004 CIHR Post-doctoral Fellowship
2000 Henry Friesen Young Scientist award for excellence in cardiovascular research
2000 E.L. Drewry Memorial Award for research excellence
2000 Merck Frosst Canada Award for Cell Biology
2000 Manitoba Medical Service Foundation award for excellence in the MMSF poster competition
1999 Manitoba Medical Service Foundation / Morris Neaman, Dr. Norman and Margaret Corne Award for research excellence

Selected Publications

Cell Stem Cell
  • Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H, Doble BW. β-Catenin Enhances Oct-4 Activity and Reinforces Pluripotency through a TCF-Independent Mechanism. Cell Stem Cell. 2011 Feb 4;8(2)214-27. PubMed PMID: 21295277
  • Zhou J, Lal H, Chen X, Shang X, Song J, Li Y, Kerkela R, Doble BW, Macaulay K, Decaul M, Koch WJ, Farber J, Woodgett J, Gao E, Force T. GSK-3alpha directlyregulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. J Clin Invest. 2010 Jun 1. pii: 41407. doi: 10.1172/JCI41407. [Epub ahead of print] PubMed PMID: 20516643.
  • Kaidanovich-Beilin O, Lipina TV, Takao K, van Eede M, Hattori S, Lalibert C, Khan M, Okamoto K, Chambers JW, Fletcher PJ, Macaulay K, Doble BW, Henkelman M, Miyakawa T, Roder J, Woodgett JR. Abnormalities in brain structure and behavior in GSK-3alpha mutant mice. Mol Brain. 2009 Nov 19;2(1):35. PubMed PMID: 19925672; PubMed Central PMCID: PMC2785804.
  • Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, Snider WD. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci. 2009 Nov;12(11):1390-7. Epub 2009 Oct 4. PubMed PMID: 19801986.
  • Shen F, Li N, Gade P, Kalvakolanu DV, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL. IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Sci Signal. 2009 Feb 24;2(59):ra8. PubMed PMID: 19244213; PubMed Central PMCID: PMC2754870.
  • Doble BW, Woodgett JR. Exploring pluripotency with chemical genetics. CellStem Cell. 2009 Feb 6;4(2):98-100. PubMed PMID: 19200796.
  • Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. Kerkela R. Kockeritz, MacAulay K, Zhou J, Doble BW, Beahm C, Greytak S, Woulfe K, Trivedi CN, Woodgett JR, Epstein HA, Force T. J Clin Invest. 2008 Oct 1.
  • Tissue-specific role of glycogen synthase kinase 3-beta in glucose homeostasis and insulin action.Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR. Mol Cell Biol. 2008 Oct:28(20);6314-28.
  • The ground state of embryonic stem cell self-renewal. Ying OL, Wray J, Nichols J, Batle-Morera L, Doble B, Woodgett J, Cohen P, Smith A. Nature. 2008 May 22;453(7194):519-23.
  • Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3beta Inactivation. Thornton T, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements J, Sabio G, Davis RJ, Matthews DE, Doble BW, Rincon M. Science. May 2008 Vol. 320 no. 5876 pp. 667-670.
  • Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes. Tanabe K, Liu Z, Patel S, Doble BW, Li L, Cras-Méneur C, Martinez SC, Welling CM, White MF, Bernal-Mizrachi E, Woodgett JR, Permutt MA. in mouse models of insulin resistance. PLoS Biol. 2008 Feb;6(2):e37.
  • Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X. Development. 2008 Jan;135(2):367-75. Epub 2007 Dec 12.
  • Cell Metabolism Oct 2007GSK 3α-Specific Regulation of Murine Hepatic Glycogen Metabolism. MacAulay, K.*, Doble, B.W.*, Patel, S., Hansotia, T., Sinclair, E., Drucker, D., Nagy, A. and Woodgett, J.R. (October 2007).  Cell Metab. 2007 Oct;6(4):329-37.  *These authors contributed equally to this work.
  • Functional Redundancy of GSK-3α and GSK-3β in Wnt/β-Catenin Signaling Shown by Using an Allelic Series of Embryonic Stem Cell Lines. Doble, B.W., Patel, S., Wood, G., Kockeritz, L., and Woodgett, J.R. (2007).   Developmental Cell. 12(5), 957-971.
  • R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X. (2007). J Biol Chem. 282(21):15903-11.
  • Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium. Kaladchibachi SA, Doble B, Anthopoulos N, Woodgett JR, Manoukian AS. (2007). J of Circadian Rhythms. 12(5), 3
  • Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Kockeritz L, Doble B, Patel S, Woodgett JR. (2006) Curr. Drug Targets. 7(11):1377-88.
  • A dual-kinase mechanism for Wnt coreceptor phosphorylation and activation. Zeng, X., Tamai, K., Doble, B.W., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J.R. and He, X.  (2005). Nature. 438(7069):873-7.

[Brad Doble's publications on Pub Med]

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