Shetuan Zhang (Queen's University)
Colin D. Funk (Queen's University)
Long QT syndrome (LQTS) is a cardiac electrical disorder that is a common cause of unexpected sudden death. LQTS can be inherited due to naturally occurring subtle alterations (mutations) in proteins called “potassium channels” in the heart. To treat this group of patients, the most straightforward approach is to correct the prolonged QT intervals. Unfortunately, there is no such a means available, and doctors only use drugs or device to prevent further worsening of the condition - life-threatening arrhythmias and sudden death.
The "potassium channel proteins" normally must accumulate to certain numbers at the cell surface for them to function properly. The alterations in protein due to mutations drastically reduce the number of proteins on the cell surface and thus cause the disease. There are two possible reasons for the reduction in channel numbers on the cell surface:
- the altered protein cannot be transported to the cell surface and trapped inside the cell;
- the altered protein can be transported to the cell surface but they are not stable there and rapidly digested by the cell.
Although it is generally thought the former is the case, we believe that the later is the case based on our recent observations. Distinguishing these two possibilities is important because different strategies will be required to enhance the protein levels on the cell surface.
The aim of our project is to establish whether some nutrition-essential food components such as fats can stabilize certain mutant proteins on the cell surface. This would enhance the amount of the proteins on the cell surface, and therefore provide a new treatment for the affected patients.
Description of the project
We will use two systems to test our hypothesis. First, we will use an established cell culture system. We will create alterations of the protein to mimic the human diseased state. We will grow the altered proteins in cells and study the effects of lipids on the amount of proteins on the cell surface. Second, we will create a rabbit model that mimics human disease. We will use components identified in the cell culture system to treat the diseased rabbits.
How the project is relevant to heart disease and stroke
In the last decade, drug-induced LQTS has been the single most frequent reason for a drug to be removed from the market. Inherited LQTS is responsible for most unexpected sudden death in young otherwise healthy individuals. By exploring a novel means using food-components to treat patients with LQTS, this project is highly relevant to the HSF's mission in eliminating heart disease and stroke and reducing their impact through the advancement of research and its application.