Chris Bleackley, PhD
Office: 467A, Medical Sciences Building
Phone: 780-492-3968 (Office)
Distinguished University Professor, Dept. of Biochemistry
Canada Research Chair in Molecular Biology
AHFMR Medical Scientist
Fellow of the Royal Society of Canada
Canadian Institutes for Health Research Distinguished Scientist
Mechanisms of cell-mediated cytotoxicity and apoptosis
We hope that by understanding how the immune system attacks islets we will be able to develop novel strategies to protect them after diabetes onset and post transplantation.
Current Research Activities
My laboratory is employing molecular genetic and biochemical techniques to investigate how T-lymphocytes perform their specific functions. The major focus at present is aimed at understanding how cytotoxic T-cells kill their targets. We reasoned that "cytotoxicity-related proteins" would be expressed specifically in these cells. Using recombinant DNA technology, we identified a number of genes which are expressed uniquely in cytotoxic cells. We identified a novel family of serine proteinases (now called granzymes), whose expression correlated with cytotoxicity, and are contained in cytoplasmic granules.
Taken together our results suggest that these genes play a key role in cytotoxicity. Current efforts are directed at understanding what part they do play in the killing mechanism, determining how the genes are organized and investigating how they are regulated (i.e., determination of important DNA regulatory sequences and detection of transacting regulatory proteins). Other mechanisms of CTL-mediated lysis are also under investigation.
T-lymphocytes play a key role in the body's defenses against disease, and are important effectors in organ transplant rejection. A knowledge of how they function may well lead to the development of new forms of rational immunotherapy. Upon interaction with a virus infected, tumor or transplanted cell, the granzymes are exocytosed and enter the cytoplasm of the target. The enzymes then cleave critical substrates that initiate both apoptotic and necrotic cell death. We have recently discovered that uptake of granzyme is in via a specific receptor. Modulation of the levels of this protein may be very useful to increase or decrease sensitivity to lymphocyte-mediated killing.
Other Activities and Affiliations
Dr. Bleackley presently holds the Canada Research Chair in Molecular Biology and is an Alberta Heritage Foundation for Medical Research Scientist, a Fellow of the Royal Society of Canada and is a Canadian Institutes for Health Research Distinguished Scientist.
PhD, Birmingham, UK
Dr. Bleackley`s recent awards include the Roche Diagnostics Award for Outstanding Research Achievements, the Cinader Immunology Award, the Kaplan Award for Research Excellence and the Robert Nobel Prize from the National Cancer Institute of Canada.
Dr. Bleackley also serves on the Advisory Board of the Institute of Infection and Immunity of the CIHR and is presently a member of the Advisory Council on Research of the NCIC.
Ramji, QA, Bayrack, K, Arefanian H, Marcet-Palacios, M, Bleackley RC, Rajotte RV, Rayat, GR. Protection of porcine islet xenografts in mice using sertoli cells and monoclonal antibodies. Transplantation. 2011 92(12): 1309-15
Ewen CL, Kane, KP, Bleackley RC A quarter century of granzymes. Cell Death Differentiation. 2012 19(1): 28-35
Thiery, J, Keefe, D, Boulant, S, Boucrot E, Walch M, Martynyalet D, Goping, IS, Bleackley RC, Kirchausen T, Lieberman J. Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nat. Immunol. 2011 12(8): 770-777
Dufour JM, Lord SJ, Kin T, Rayat GR, Dixon DE, Bleackley RC, Korbutt GS, Rajotte RV. Comparison of successful and unsuccessful islet/Sertoli cell cotransplant grafts in streptozotocin-induced diabetic mice. Cell Transplant. 2008 16(10): 1029-38
Goping, IS, Sawchuk T, Reiger A, Shostak I, Bleackley RC. Cytotoxic T lymphocytes overcome Bcl-2 inhibition: target cells contribute to their own demise. Blood. 2008 15;111(4): 2142-51
Sipione S, Simme KC, Lord SJ, Motyka B, Ewen C, Shostak I, Rayat GR, Dufour JM, Korbutt GS, Rajotte RV, Bleackley RC. Identification of a novel human granzyme B inhibitor secreted by cultured sertoli cells. J. Immunol 2006 15;177(8) 5051-8
Marcet-Palacios M, Duggan BL, Shostak I, Barry M, Geskes T, Wilkins JA, Yanagiya A, sonenberg N, Bleackley RC. Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3. PLoS Pathog. 2011 7(12): e1002447
Mader JS, Ewen C, Hancock RE, Bleackley RC. The human cathelicidin LL-37, induces granzyme-mediated apoptosis in regulatory T cells. J. Immunother. 2011 34(3): 229-35
Mader JS, Marcet-Palacios M, Hacock RE, Bleackley RC. The cathelicidin LL-37, induces granzyme-mediated apoptosis in cytotoxic T lymphocytes. Exp Cell Res 2011 15;317(4) 531-538
Department of Biochemistry