Dr. Michael Czubryt
Interim Executive Director of Research
St. Boniface Hospital
Molecular Pathophysiology, Institute of Cardiovascular Sciences
Department of Physiology, University of Manitoba
Dr. Czubryt’s lab is interested in how the proper or improper functioning of genes contributes to the development of heart diseases. Genes are the instruction manuals for cells and tissues – they provide direction for how to make things such as proteins (which do everything from contributing to the physical structure of cells to converting energy into work). However, encoded in genes is also the information on when to make proteins, and in which tissues they should be made – in this way, heart proteins are only made in the heart, and only when needed. His lab studies how the control mechanisms that turn genes on and off can contribute to heart diseases by being activated inappropriately.
Special regulatory proteins (transcription factors) interpret the information encoded within genes in order to control how, when and where genes are turned on or off. These proteins can thus have very powerful effects on how cells and tissues function. Inappropriate activation or inhibition of these proteins can contribute to all aspects of the disease process, yet at the same time, controlling the activity of these regulators may provide novel means to combat disease.
Why is this work important?
Great strides have been made in improving treatments for various cardiovascular diseases. Despite this success, however, cardiovascular diseases still are responsible for approximately one-third of all natural deaths. In order to generate new treatments, we need to better understand not only how the heart works as a whole, but to also better define how the individual types of heart cells work. A key to this understanding is how the activity of our thousands of genes is orchestrated in each cell type. This work will identify new targets for therapy by allowing us to come at the problem from a new direction.
What techniques and equipment are used in this laboratory?
The techniques used in Dr. Czubryt’s laboratory enable them to perform highly detailed analyses of gene function. For example, they can examine the regulatory regions of genes to identify areas that control when and where a gene is turned on. Using this knowledge, they can specifically turn genes of interest on or off in isolated heart cells, or in the hearts of animal models such as mice, in order to determine the functions of those genes. If the loss of a gene causes symptoms of heart failure, then the lab can focus on this gene in human heart failure patients to determine whether it plays a role in progression of the disease. They can then also explore ways to restore the proper function of this gene to better treat patients.
A powerful tool in his laboratory is a microarray analysis system. Microarrays allow them to take a “snapshot” of nearly all the genes in a sample such as heart tissue – they can quickly get an accurate and reliable measure of the degree to which each gene is “on” or “off” for tens of thousands of genes at once. By comparing the snapshots from a healthy heart compared to a diseased heart, they can determine which genes show altered activation between the two. Using computer analysis, they can then focus on clusters of genes that are involved in specific processes, for example energy production, and gain an understanding of which processes may be important in the development of the disease. This approach allows the Czubryt lab to perform analyses in three days which only a few years ago would have taken many years to complete. An added benefit is that this tool can be used for any tissue – they can thus assist researchers who study other diseases such as cancer, Alzheimer disease or diabetes.
About Dr. Czubryt
Dr. Michael Czubryt was born and raised in Winnipeg. After completing a B.Sc. (Honours) in Biotechnology at the University of Manitoba, he went on to obtain a Ph.D. in Cardiovascular Pathophysiology under Dr. Grant Pierce. He completed his training as a postdoctoral fellow at the University of Texas Southwestern Medical Center at Dallas under Dr. Eric Olson, and has been on faculty at the University of Manitoba since 2003.
For more information, please contact:
Dr. Michael Czubryt
Tel. (204) 235-3719
Fax. (204) 231-1151
Fibrosis of the heart occurs when strong fibers (made mainly of a protein called collagen) are constructed throughout the heart by cells called fibroblasts. Normally these fibers provide strength to the heart, but in response to stresses such as high blood pressure, these fibers are made in excess. This results in stiffening of the heart, which makes both contraction and relaxation difficult during each beat. Over time, this increased workload can result in heart failure. At present there are no treatments for fibrosis of the heart.
Dr. Czubryt’s laboratory has discovered a critical protein regulator called scleraxis which acts as a transcription factor to turn on collagen genes in the heart. Their work has shown that this regulator is activated during cardiac stress such as heart attack or high blood pressure. Scleraxis appears to work by responding to stress signals and increasing collagen production. The Czubryt lab has also created a mutant form of scleraxis which interferes with collagen production – the first step in creating a therapy aimed at blocking or reducing fibrosis.
Interestingly, Dr. Czubryt’s lab is gathering evidence that scleraxis may play a role in fibrosis in other tissues, such as the lungs. This project may thus have implications for therapies in multiple diseases besides those of the heart.
Enlargement of the Heart in Disease
Besides fibrosis, another hallmark of heart disease is enlargement, which occurs when the contracting cardiomyocytes (heart cells) increase in size in response to stress. Following exercise or during pregnancy, enlargement of the heart is both normal and beneficial – the heart enlarges in order to deal with an increase in workload. In disease, however, enlargement actually impairs the ability of the heart to do its job. Exactly how and why these differences occur is not yet fully understood, but different genes and signaling pathways are known to be involved.
The Czubryt lab is investigating a novel regulator of cardiomyocyte enlargement called AKAP121. This protein acts as a signaling junction point, and their studies have shown that its loss results in activation of a transcription factor that drives the cell enlargement process. AKAP121 appears to be lost in response to stress, but exactly how this occurs is unclear. Furthermore, this loss results in changes in metabolism of heart cells, again through an unknown mechanism.
Under normal conditions, the heart relies on fat for most of its supply of energy, but it is also able to burn sugars such as glucose and other substrates if and when they are available. In certain diseases such as heart failure, the heart shifts its energy requirements to sugars and away from fat. Dr. Czubryt is investigating whether AKAP121 may tie together changes in cell growth (by promoting heart cell enlargement) with altered energy usage by altering the activation of genes involved in fuel selection and usage. This would help explain why the enlarged heart functions poorly – different signals would be driving increased protein production to support cell enlargement, while at the same time resulting in inefficient fuel usage, effectively starving the heart when its workload is highest.
Bagchi RA, Czubryt MP: Synergistic roles of scleraxis and Smads in the regulation of collagen 12 gene expression. Biochim Biophys Acta Mol Cell Res, In press, 2012
Berry JM, Le V, Rotter D, Battiprolu PK, Grinsfelder B, Tannous P, Burchfield JS, Czubryt M, Backs J, Olson EN, Rothermel BA, Hill JA: Reversibility of adverse, calcineurin-dependent cardiac remodeling. Circ Res 109:407-417, 2011
Czubryt MP, Lamoureux L, Ramjiawan A, Abrenica B, Jangamreddy J, Swan K: Regulation of cardiomyocyte Glut4 expression by ZAC1. J Biol Chem 285:16942-16950, 2010
Espira L, Lamoureux L, Jones SC, Gerard RD, Dixon IMC, Czubryt MP: The basic helix-loop-helix transcription factor scleraxis regulates fibroblast-mediated collagen synthesis. J Mol Cell Cardiol 47:188-195, 2009
Abrenica B, AlShaaban M, Czubryt MP: The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy. J Mol Cell Cardiol 46:674-681, 2009
MEF2C transcription factor controls chondrocyte hypertrophy and bone development:Arnold MA, Kim Y, Czubryt MP, McAnally J, Qi X, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN, Dev Cell 12:377-389, 2007.
The role of sex in cardiac function and disease: Czubryt MP, Espira L, Lamoureux L, Abrenica B: Can J Physiol Pharmacol 84:93-109, 2006.
Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers: Oh M, Rybkin I, Copeland V, Czubryt MP, McAnally J, Shelton J, Hill JA, deWindt LJ, Bassel-Duby R, Olson EN, Rothermel BA: Mol Cell Biol 25:6629-6638, 2005.
Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice: Li C, Czubryt MP, McAnally J, Bassel-Duby R, Richardson JA, Wiebel FF, Nordheim A, Olson EN: Proc Natl Acad Sci USA 102:1082-1087, 2005.
Balancing contractility and energy production: the role of MEF2 in cardiac hypertrophy. Czubryt MP, Olson EN: Recent Prog Horm Res 59:105-124, 2004.
Regulation of peroxisome proliferator-activated receptor g coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5. Czubryt MP, McAnally J, Fishman GI, Olson EN: Proc Natl Acad Sci USA 100:1711-1716, 2003.
Merit Award for Service, University of Manitoba, 2009
Young Investigator Award, Canadian Cardiovascular Society, 2006
Wilbert J. Keon Symposium Award for Basic Scientists, CIHR National Research Forum for Young Investigators in Circulatory and Respiratory Health, 2005
New Investigator Award, Heart and Stroke Foundation of Canada, 2004
McDonald Scholarship for highest-ranked New Investigator in Canada, Heart and Stroke Foundation of Canada, 2004
Distinguished Dissertation Award for Health Sciences, University of Manitoba, 2001
E.L. Drewry Memorial Award for Graduate Medicine, University of Manitoba, 2000
St. Boniface Hospital Foundation Inc. Award for Cardiovascular Biology, 2000
We gratefully acknowledge support from the following agencies, without whom we could not perform our studies:
Canadian Institutes of Health Research Operating Grant (2004-2007; 2007-2009; 2007-2012; 2010-2013; 2019-2024)
Mayo-St. Boniface CANUSA Grant (2012-2014)
Juvenile Diabetes Research Fund (2011-2014)
Dean of Medicine Equipment Innovation Fund, U. Manitoba (2011)
Heart and Stroke Foundation of Canada (2006-2008)
Manitoba Health Research Foundation Establishment Grant (2006-2008)
Canadian Foundation for Innovation New Opportunities Fund (2005)
University of Manitoba Research Grant Program (2004-2005)
Manitoba Medical Service Foundation (2004)
St. Boniface General Hospital and Research Foundation Start-up Funds
University of Manitoba Faculty of Medicine Start-up Funds