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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 lab studies the structure and function of endoplasmic reticulum (ER) membranes and the role of this membrane system in the control of intracellular signalling, communication with other intracellular organelles, regulation of protein synthesis and folding, modulation of gene expression and calcium homeostasis. The ER plays a vital role in many cellular processes, including Ca2+ signaling lipid biosynthesis; and protein synthesis, folding, and post-translational modification. Most importantly, the ER can detect and integrate incoming signals, generate output signals in response to environmental changes, and can even modulate its own luminal dynamics. How the ER affects the balance between anti- versus pro-apoptotic signals, and therefore between adaptive and maladaptive cellular responses, remains a crucial question in pathophysiology and in cell biology. ER stress is associated with many severe human pathologies including heart disease, metabolic disorders, cancer and neuropathies. The multifunctional nature of the ER has enabled us to help identify the contribution of several ER associated proteins to the maintenance of ER homeostasis in health and disease. We discovered that ER resident chaperones play critical roles in cardiac development and pathophysiology of the mature heart. The proteins are also key in specific neuropathies. Currently, the focus of our lab is on the role of ER associated molecular chaperones (calreticulin, calnexin and others) and ER stress in cardiac and nervous system physiology and pathophysiology. Our long-term goal is to understand ER stress and ER signaling events responsible for the activation and maintenance of intracellular pathways affecting cardiac or neuronal physiology and pathology, and to use this information to devise pharmacological and genetic therapies for the treatment of human disease.
 
Current Studies
Here are a few examples of research projects currently being pursued in our lab:
 
Modulators of ER stress
Using small interfering RNA (siRNA) library screens, we have identified several cellular proteins that regulate ER stress responses and the unfolded protein response (UPR), including ER luminal resident chaperones and folding enzymes. We are pursuing a variety of strategies to use this information to manipulate ER stress pathways and to uncover additional regulators of ER stress.
 
Calreticulin, ER resident proteins and cardiac physiology.
We apply gene knockout and transgenic techniques to understand the role of ER proteins and the ER luminal environment in embryogenesis and congenital pathologies. We discovered that calreticulin is critical for cardiac development. Modulation of calreticulin expression in the heart results in development of severe cardiomyopathies and complete heart block. We are investigating the contribution of calreticulin and other ER resident proteins to cardiac pathology including cardiac hypertrophy and heart failure.
 
ER calcium homeostasis
Intracellular Ca2+ is an important second messenger. Ca2+ is released from the ER into the cytoplasm and the loss of ER Ca2+ stores necessitates refilling via a process known as store-operated Ca2+ entry (SOCE). Stromal interaction molecule 1 (STIM1) is an ER membrane Ca2+ sensor responsible for activation of store-operated Ca2+ influx. We discovered that STIM1 oligomerization and SOCE are modulated by the ER resident oxidoreductase ERp57. We are interested in understanding the role of ER luminal environment in regulation of ER-dependent Ca2+ signaling and its role in human pathology.
 
ER chaperones and energy metabolism
Disrupted ER homeostasis due to loss of ER chaperones may lead to dysregulation of energy metabolism. We are interested in the mechanisms responsible for ER-dependent modulation of energy metabolism with a special emphasis on the role of ER associated molecular chaperones.
 
Deciphering a role of ER chaperones in neuropathies
We discovered that calnexin-deficient mice develop a specific neuropathy, dysmyelination and impaired motor function. We are interested in understanding the role of calnexin and ER stress in the pathology of the nervous system with a special emphasis on human neuropathies such as Multiple Sclerosis, amyotrophic lateral sclerosis (ALS) and myelin diseases.

 

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:
Groenendyk, J., Peng, Z., Dudek, E., Fan, X., Mizianty, M.J., Dufey, E., Urra, H., Sepulveda, D., Rojas-Rivera, D., Yunki, L., Kim, D.H., Baretta, K., Srikanth, S., Gwack, G., Ahnn, J., Kaufman, R.J., Lee, S-K., Hetz, C., Kurgan, L. and Michalak M. 2014. Interplay between PDIA6 and miR-322 controls adaptive response to disrupted endoplasmic reticulum calcium homeostasis. Science Signaling. 7 (329): ra54
 
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