Dr. Michael Czubryt, Molecular Pathophysiology

Dr. Michael Czubryt

Executive Director of Research
St. Boniface Hospital

Principal Investigator
Molecular Pathophysiology, Institute of Cardiovascular Sciences

Professor
Department of Physiology, University of Manitoba

Research Focus

Dr. Czubryt’s lab is interested in how the altered function 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 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 the 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 previously 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’s 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
Email. mczubryt@sbrc.ca

In Detail

Combatting Fibrosis

The heart is made up of a variety of cell types. The two most common are the heart muscle cells, which are responsible for the beating of the heart, and fibroblasts, which perform a variety of support functions, including the construction of a protein-rich support structure called the extracellular matrix. This matrix normally provides strength to the heart, which develops high internal pressures during every one of its one hundred thousand contractions each day.

Fibrosis of the heart occurs when fibroblasts detect stress or injury, such as may occur in high blood pressure or after a heart attack, and alter their function to become a myofibroblast – a highly active form of fibroblast that produces much higher levels of matrix proteins. The excessive creation of these proteins by myofibroblasts causes stiffening of the heart walls, which in turn interferes with both contraction and relaxation during each beat. Over time, this increased workload can result in heart failure, and the excessive matrix proteins can interfere with the electrical activity of the heart that governs the heartbeat. Fibrosis is now recognized as a specific risk factor for arrhythmias, heart failure, hospitalization and death. 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 a number of 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 made in fibroblasts causes them to become myofibroblasts, and it does so by activating a number of genes involved in the fibrosis process. Recent work from the Czubryt lab has shown that removing scleraxis from fibroblasts blocks fibrosis from occurring, or from getting worse, by preventing the appearance of myofibroblasts, suggesting that scleraxis may be an important target for developing anti-fibrosis medications.

Interestingly, Dr. Czubryt’s lab is gathering evidence that scleraxis may play a role in fibrosis in other tissues, such as the lungs and skin. This project may thus have implications for therapies in multiple diseases besides those of the heart.

Key Publications

Nagalingam RS, Chattopadhyaya S, Al-Hattab DS, Cheung DYC, Schwartz LY, Jana S, Aroutiounova N, Ledingham DA, Moffatt TL, Landry NM, Bagchi RA, Dixon IMC, Wigle JT, Oudit GY, Kassiri Z, Jassal DS, Czubryt MP: Scleraxis and fibrosis in the pressure overloaded heart. In press Eur Heart J 2022.

Al-Hattab DS, Chattopadhyaya S, Czubryt MP: Canadian contributions in fibroblast biology. Cells 11:2272, 2022.

Rabinovich-Nikitin I, Blant A, Dhingra R, Kirshenbaum LA, Czubryt MP: NF-kB p65 attenuates cardiomyocyte PGC-1a expression in hypoxia. Cells 11:2193, 2022.

Chattopadhyaya S, Nagalingam RS, Ledingham DA, Moffatt TL, Al-Hattab DS, Narhan P, Stecy MT, O’Hara KA, Czubryt, MP. Regulation of cardiac fibroblast GLS1 expression by scleraxis. Cells 11:1471, 2022.

Czubryt MP, Stecy T, Popke E, Aitken R, Jabusch K, Pound R, Lawes P, Ramjiawan B, Pierce GN: N95 mask reuse in a major urban hospital – COVID-19 response process and procedure. J Hosp Infect 106:277-282, 2020.

Al Qudah M, Hale TM, Czubryt MP: Targeting the renin-angiotensin-aldosterone system in fibrosis. Invited review. Matrix Biol 91-92:92-108, 2020.

Czubryt MP: Cardiac fibroblast to myofibroblast phenotype conversion – an unexploited therapeutic target. J Cardiovasc Dev Dis 6:28, 2019.

Al Hattab DS, Safi HA, Nagalingam RS, Bagchi RA, Czubryt MP: Scleraxis regulates Twist1 and Snail1 expression in epithelial-to-mesenchymal transition. Am J Physiol Heart Circ Physiol 315:H658-H668, 2018; subject of an Editorial in Am J Physiol Heart Physiol, 2018; featured as the Article of the Week for Am J Physiol Heart Circ Physiol, 09/06/18.

Nagalingam RS, Safi HA, Al-Hattab DS, Bagchi RA, Landry NM, Dixon IMC, Wigle JT, Czubryt MP: Regulation of cardiac fibroblast MMP2 gene expression by scleraxis. J Mol Cell Cardiol 120:64-73, 2018.

Safi H, Nagalingam RS, Czubryt MP: Scleraxis: a force-responsive cell phenotype regulator. Curr Opin Physiol 1:104-110, 2018. Invited review.

Roche PL, Nagalingam RS, Bagchi RA, Belisle BMJ, Aroutiounova N, Wigle JT, Czubryt MP: Role of scleraxis in mechanical stretch-mediated regulation of cardiac myofibroblast phenotype. Am J Physiol Cell Physiol 311:C297-C307, 2016; featured as the Image of the Week for Am J Physiol Cell Physiol, July 2016.

Bagchi RA, Lin J, Wang R, Czubryt MP: Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis. Cell Tissue Res 366:381-391, 2016.

Bagchi RA, Roche P, Aroutiounova N, Espira L, Abrenica B, Schweitzer R, Czubryt MP: The transcription factor scleraxis is a critical regulator of cardiac fibroblast phenotype. BMC Biol 14:21, 2016.

Bagchi RA, Wang R, Jahan F, Wigle JT, Czubryt MP: Regulation of scleraxis transcriptional activity by serine phosphorylation. J Mol Cell Cardiol 92:140-148, 2016; subject of an Editorial in J Mol Cell Cardiol 93:106-107, 2016.

Patents

USA Patent 9,238,685: Inhibition of collagen synthesis. Issued January 19, 2016. Inventor: Michael P. Czubryt.

USA Patent 9,737,586: Inhibition of collagen synthesis. Issued August 22, 2017. Inventor: Michael P. Czubryt.

USA Patent 9,993,521: Modulation of scleraxis using a dominant negative scleraxis mutant with a basic DNA-binding domain deletion. Issued June 12, 2018. Inventor: Michael P. Czubryt.

Jan Slezak Award for Excellence in Cardiovascular Sciences, International Academy of Cardiovascular Sciences, 2021

Andras Varro Award for Excellence in Cardiovascular Sciences, International Academy of Cardiovascular Sciences, 2019

Merit Award for Service, University of Manitoba, 2019, 2014, 2009

Award for Scientific Excellence, University of Mississippi Medical Center, 2017

Fellow, International Academy of Cardiovascular Sciences, 2016

Fellow, American Heart Association, 2016

Ronald Duhamel Innovation Fund Award, 2016

Sanofi BioGENEius Challenge Mentorship Award, 2015, 2014

Distinguished Service Award, International Academy of Cardiovascular Sciences, 2014

Fellow, American Physiological Society Cardiovascular Section, 2013

Young Investigator Award, Canadian Cardiovascular Society, 2006

Heart and Stroke Foundation of Canada McDonald Scholarship, 2004

Heart and Stroke Foundation of Canada New Investigator Award, 2004

We gratefully acknowledge critical support over many years from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Heart and Stroke Foundation of Canada, Research Manitoba/Manitoba Health Research Council, the University of Manitoba, and the St. Boniface Hospital Foundation.