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Marek Michalak

Michalak.jpg
Distinguished University Professor
Ph.D., Nencki Institute
M.Sc. University of Warsaw
 
 
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
355 Medical Sciences Building
Edmonton, Alberta, Canada  T6G 2H7
 
Tel: 780.492.2256
Lab Tel: 780.492.3481
Fax:  780.492.0886
 
Research:
 
Our laboratory focusses on understating the molecular events associated with endoplasmic reticulum (ER) protein quality control and its relationship to pathological conditions affecting cardiac and nervous systems, and the development of therapies to prevent this damage. Many severe protein folding diseases are the product of mutations resulting in impaired function of the quality control and ER stress response machinery including vascular diseases such as myocardial infarction and atherosclerosis; neurodegenerative diseases, such as Alzheimer’s and Charcot-Marie Tooth Disease; systemic disease, such as cystic fibrosis; prion diseases such as bovine spongiform encephalopathy and the human variant, Creutzfeldt-Jakob disease; as well as cancer. The ER is also the first compartment in the protein secretory pathway involved in cellular signaling and organelle-organelle communication including activation of transcriptional processes. The ER is also intimately involved in calcium signaling and communication with the plasma membrane calcium channels. The ER is a multifunctional organelle able to detect and integrate incoming signals, modulate its own luminal dynamics and generate output signals in response to environmental changes.
 
Our work is focused on ER membrane and ER associated molecular chaperones and folding enzymes calreticulin, calnexin and ER associated oxidoreductases. We investigate the dynamics of the ER lumen with emphasis on protein-protein interactions, role of ions and nucleotides in the control of the ER function. Using transgenic and gene knockout and stem cells approaches we discovered that ER membrane-associated proteins play an important role in embryogenesis, cardiac development, cardiac physiology and pathology and in specific neuropathies. Presently our approach is to investigate the structure and function of the ER luminal proteins at virtually every level of biological complexity. We examine the role of ER protein at the single cell level using molecular biological, biochemical, immunological and biophysical techniques. We also utilize gene knockout and transgenic techniques to examine the role of the ER proteins at the whole animal level. Calreticulin deficient mouse have a lesion in cardiac development. Calreticulin gain-of-function in the heart leads to sever cardiomyopathies and heart failure. It is likely that ER proteins may become the targets for clinical management of hypertrophy and failing heart, especially in children. Calnexin-deficient mouse develop neurological problems reminiscent of myelin diseases such as Charcot-Marie Tooth. One important focus of our studies is on the role of molecular chaperones in the pathology of myelin diseases including Multiple Sclerosis. Finally, knockout of the ERp57 gene encoding oxidoreductase indicate that this protein plays critical role in energy metabolism and modulation of calcium homeostasis.
to investigate the function of ER associated chaperones, calreticulin, calnexin and ERp57, and their role in cardiac and neuronal differentiation. In this capacity we are developing in vitro and in vivo ES cell models for future cell therapies in cardiovascular and neuronal systems.
 
Lab Members:
Monika Dabrowska, Technical
Elzbieta Dudek, Postdoctoral Fellow
Jody Groenendyk, Research Associate
Joanna Jung, Post Doctoral Fellow
Dukgyu Lee, Post Doctoral Fellow
Daniel Prins, Graduate Student
Alison Robinson, Technical
Wen-An (Jennifer) Wang, Graduate Student
 
 
 
 
 


Selected Publications:
Lee, D., Oka, T., Hunter, B., Robinson, A., Papp, S., Nakamura, K., Srisakuldee, W., Nicke, B.E., Light, P.E., Dyck, J.R.B., Lopaschuk, G.L., Kardami, E., Opas, M. and Michalak, M. 2013. Calreticulin induces dilated cardiomyopathy. PLoS ONE, 8:e56387
 
Groenendyk, J., Agellon, L.B. and Michalak, M. 2013. Coping with endoplasmic reticulum stress in the cardiovascular system. Annu. Rev. Physiol75: 49-67
 
Greives MR, Samra F, Pavlides S, Blechman KM, Naylor SM, Woodrell C, Cadacio C, Gorovets D, Levine JP, Michalak M, Warren SM and Gold L.I. 2012. Exogenous calreticulin improves diabetic wound healing. Wound Repair & Reg. 20: 715-730
 
Lee, D. and Michalak, M. 2012. Calcium and bioenergetics: From endoplasmic reticulum to mitochondria. Animal Cells Syst16: 269-273
 
Coe, H., Schneider, J.D., Dabrowska, M., Groenendyk, J., Jung, J. and Michalak, M. 2012. Role of cysteine amino acid residues in calnexin. Mol. Cell. Biochem.359: 271-281
 
Millott, R., Dudek, E. and Michalak, M. 2012. The endoplasmic reticulum in cardiovascular health and disease. Can. J. Physiol. Pharmacol90: 1209-1217
 
Wang, W-A., Groenendyk, J. and Michalak, M. 2012.Calreticulin signaling in health and disease. Int. J. Biochem. Cell Biol44: 842-846
Li H-D, Liu W-X and Michalak M. 2011. Enhanced clathrin-dependent endocytosis in the absence of calnexin. PLoS ONE 6:e21678
 
Groenendyk J and Michalak M. 2011. A Genome-wide siRNA screen identifies novel phospho-enzymes affecting Wnt/?-catenin signaling in mouse embryonic stem cells. Stem Cell Rev. Rep. 7:910-926
 
Jung J, Coe H and Michalak M. 2011. Specialization of endoplasmic reticulum chaperones for the folding and function of myelin glycoproteins P0 and PMP22. FASEB J. 25:3929-3937
 
Prins D, Groenendyk J, Touret N and Michalak M. 2011. Endoplasmic reticulum luminal environment-dependent regulation of STIM1 and capacitative Ca2+ entry. EMBO Rep. 12:1182-1188
 
Coe H, Jung J, Groenendyk J, Prins D and Michalak M. 2010. ERp57 modulates STAT3 signalling from the lumen of the endoplasmic reticulum. J. Biol. Chem. 285:6725-6738
 
Kraus A, Groenendyk J, Bedard K, Baldwin TA, Krause K-H, Dubois-Dauphin M, Dyck J, Gosgnach S, Rosenbaum EE, Korngut L, Colley NJ, Zochodne D, Todd K, Agellon LB and Michalak M. 2010. Calnexin deficiency leads to dysmyelination. J. Biol. Chem. 285:18928-18938
 
Groenendyk J, Sreenivasiah PK, Kim DH, Agellon LB and Michalak M. 2010. Biology of endoplasmic reticulum stress in the heart. Circ. Res. 107:1185-1197