Grant: Operating Grant

Our study investigates the protein that is responsible for removal of acid from cells. As a byproduct of cell metabolism, acid is produced. Too much acid has detrimental effects on many cellular tissues including the heart. The protein that removes the acid from cells is called the Na+/H+ exchanger. This protein removes the excess inside acid in exchange for an outside sodium (salt). Through a series of reactions, too much salt inside a cell leads to too much calcium inside and this damages cells, especially heart cells during heart disease. Thus, the Na+/H+ exchanger protein is critically involved in heart disease. Several companies have developed drugs to inhibit the activity of this protein - which results in improved outcome in heart disease in animal models. However, when used in humans, those drugs had detrimental side effects that outweighed their beneficial effects. Similar to a complicated car, if you can't understand how something works, it is difficult to fix. Our study therefore investigates how the protein works, and what parts of the protein are important in function. We change parts of the protein to determine how they function. We measure how the changed protein works in cells. We are also expressing the protein in large amounts, to essentially get a good quality picture of the protein through high resolution imaging techniques for small molecules. Reaction with specific chemicals also gives us a picture of what parts of the protein are facing outside of the cell, and what parts are facing towards the inside of the cell. Our study will give new information on this physiologically important protein. A better picture and understanding of the protein will ultimately lead to better design of drugs that inhibit the protein. We will also provide valuable fundamental knowledge on how this human membrane protein functions.