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Dr. Michael Czubryt
Principal Investigator, Molecular Pathophysiology
Institute of Cardiovascular Sciences
Research Focus
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.
The heart has extremely high demands for energy, so the production and use of energy in heart cells is very tightly controlled. One method to control these processes is by regulating which genes are turned on and off. For example, the heart typically prefers to use fat as an energy source, but can increase its dependence on other fuels such as sugars following a heart attack – a switch that is governed in part by altering which genes are active in heart cells. Switching to sugars has the benefit that less oxygen is consumed – an important consideration in the oxygen-starved heart following a heart attack. However, sugars are also poorer energy sources than fats, so the heart has to make do with a decreased energy supply, which may contribute to further impairment of heart function over time. One Dr. Czubryt’s central ideas is that decreased efficiency in either energy production or energy consumption contributes to diseases such as enlargement of the heart (hypertrophy) or heart failure (in which the heart is unable to pump enough blood to meet the demands of the body).
Why is this work important?
By determining how genes are turned on and off, Dr. Czubryt hopes to better understand why heart function diminishes, leading to heart failure. He and his lab staff are trying to determine which changes in gene function directly contribute to the progression of heart disease, and which changes is the result of an already established disease process. They also hope to be able to design therapies aimed at restoring normal gene function in order to treat heart diseases, leading to improvements in longevity and quality of life for heart failure patients for whom current treatments are limited.
What techniques and equipment are used in this laboratory?
The techniques used in Dr. Czubryt’s laboratory enable them 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
[t]: 204-235-3719
[f]: 204-231-1151
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In Detail
UNDERSTANDING METABOLISM IN THE HEART
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. It has been known for a while that certain diseases such as heart failure result in the heart shifting its energy requirements to sugars and away from fat, but it is unclear whether these changes are a contributing factor or an adaptation as a result of the disease.
FOLLOWING A NEW PATHWAY
Dr. Czubryt has been studying a mouse model in which fundamental alterations in the metabolism of the heart due to changes in gene expression lead to heart failure. These studies have identified a new pathway that regulates metabolism in the heart involving a gene called MEF2. “MEF2 is known to play a role in hypertrophy, or enlargement of the heart, which often precedes heart failure,” notes Dr. Czubryt. “But how it plays this role is unknown.” These latest studies have shown that MEF2 helps control fat metabolism in the heart by regulating the expression of proteins involved in the breakdown of fats to produce energy. Blocking the action of MEF2 resulted in heart failure in the mice. The next step is to identify how changes in the level or activity of MEF2 itself occur, and whether these changes may predispose one to disease.
Another finding of this study suggests that there may be fundamental differences between men and women in how fat metabolism in the heart is controlled. When the action of MEF2 in the heart is blocked, male mice die significantly sooner than female mice do. Dr. Czubryt’s laboratory will examine how female hormones like estrogen may regulate this process, and whether these differences may affect susceptibility to different forms of heart failure. These experiments may one day lead to different forms of treatment for heart failure or hypertrophy that are targeted specifically to men or women.
Dr. Czubryt’s lab is also working to identify new MEF2-regulated genes in order to determine what other roles MEF2 may play, both in the healthy heart and in disease. Two promising candidates currently being examined play roles in gene expression and, potentially, hypertrophy. It was initially thought that blocking the action of MEF2 may block the development of hypertrophy, but surprisingly, genes that comprise the hypertrophic response appeared to be turned on. One of the two candidates being studied may hold the key to this mystery: it may block the hypertrophic pathway, but when the gene that codes for it is turned off by blocking MEF2, the pathway may become activated. These studies may identify new methods by which hypertrophy is turned on, which may in turn lead to improved understanding of what is occurring in human diseases.
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