Past Winner
2008 NSERC Doctoral Prize

Karim Mekhail

Cellular and Molecular Medicine

University of Ottawa

Karim Mekhail

Human cells have sophisticated strategies for coping when they get too little oxygen. Work done by Karim Mekhail at the University of Ottawa has led to a better understanding of those strategies, which could enhance our ability to use the body's natural processes to combat certain clinical conditions. His discoveries have earned him an NSERC Doctoral Prize.

Cells face oxygen shortages for different reasons, including exercise, the growth of tumours, and "ischemic" disorders such as anemia, stroke or diabetes where the normal flow of blood is impeded. When this happens, cells change some of their internal processes, including the location and function of certain proteins.

One of those proteins is called hypoxia-inducible factor (HIF), a normally inactive protein that gets activated when oxygen levels drop. It then switches on various genes in the nucleus of the cell to regulate its metabolism and stimulate the formation of blood cells and vessels. These changes initially help prevent tissue damage and, over the long term, help restore normal oxygen levels.

When oxygen levels return to normal, a second protein known as VHL recognizes and breaks down the HIF, and the cell resumes life as normal.

This HIF-VHL interaction is a good news-bad news scenario. On the plus side, it helps prevent tumors from appearing and growing. However, it can also slow down recovery from conditions such as stroke. That makes it important to understand exactly what turns the HIF protein on and off and where VHL fits into the picture, topics that Dr. Mekhail's research has revealed fascinating new details about.

The key lies in the fact that an oxygen-starved cell becomes more acidic. Under these conditions, the cell's energy demands shrink and VHL molecules are "trapped" by its nucleolus, leaving the HIF free to interact with its target genes and activate them. This phenomenon is reversed when the pH level returns to normal.

In addition to explaining the role of acidity in regulating the VHL-HIF interaction, Dr. Mekhail's work has identified other proteins that can be controlled by the acidity "trap." This paves the way for the development of therapies that can either boost or suppress this natural response as needed, thereby helping patients recover from ischemic disorders or inhibiting cancer cells from growing.