Vollum Institute researcher Matt Whorton, Ph.D. was recently presented with an American Asthma Foundation (AAF) Scholar Award for his work on the structure and function of adenylyl cyclase. This highly competitive award supports basic research with potential applications to the study of asthma. We recently sat down with Whorton to discuss his research and learn more about his AAF project.
The AAF Scholar Award is a unique funding opportunity for basic scientists. Can you tell us about it?
Yes, the Foundation tries to attract people not already in the field by inviting applications that are innovative and that approach the disease from a new angle.
What research are you involved in and how does it pertain to the field of asthma?
I focus on protein mechanisms – how proteins work and how they’re regulated. I’m particularly interested in proteins embedded in cell membranes that are involved in transporting molecules or ions across these membranes.
The primary focus of my AAF award will be to examine a membrane protein called adenylyl cyclase. I’ve known about this protein for a while from having worked with a class of receptors called G-protein coupled receptors when I was in graduate school. These receptors are widespread throughout the body and expressed in cell membranes. They respond to ligands and drugs outside the cell and pass the information inside the cell. One thing these receptors do is activate other proteins, and one of the main targets is adenylyl cyclase. This activation then leads to the creation of a molecule, cyclic AMP, which can diffuse into the cell and does a number of things depending on the cell type and tissue.
These systems are all over the body but are particularly important in the lungs, because when cyclic AMP is produced, it causes the airway muscles to relax, making them wider and allowing for easier breathing. People with asthma have constricted airways, either because they have too much mucus or because these systems are deficient and the muscles are always contracted. The current drug treatment for asthma is the use of beta agonists, which activate these receptors to turn on the production of cyclic AMP. But up until now, people haven’t really looked at adenylyl cyclase from a mechanistic point of view in terms of how the whole protein works and how it’s regulated, because it happens to be regulated by many different types of inputs and therefore poorly understood. So, my initial goal is to see at an atomic level what the protein looks like and then how its conformation is regulated by other proteins in the cell to either enhance or inhibit the creation of cyclic AMP. Since cyclic AMP is so important in controlling smooth muscle tone and is central to how asthma is treated, understanding how it’s regulated has the potential to lead to new therapeutics for across the asthma spectrum as well as other lung diseases such as Chronic Obstructive Pulmonary Disease.