A Florida State University biochemist who studies a group of proteins linked to several inherited diseases has received a major grant to advance his research toward a better understanding of cellular secretion, which is linked to a wide range of diseases. That research could one day lead to new treatments for those diseases.
Scott Stagg, an assistant professor in the Department of Chemistry and Biochemistry, has been awarded a five-year, $1.3 million grant by the National Institutes of Health to study a group of proteins that play a critical role in the proper functioning of cell membranes in the human body. The so-called COPII proteins operate within the secretory pathway, which is a mechanism used by cells to move other proteins from the inside of the cell to the outside – a process known as secretion. When genetic mutations of the COPII proteins occur, this secretion process is inhibited, leading to disease.
“Secretion is one of the most basic and critical processes in all eukaryotic cells,” Stagg said, explaining that eukaryotes include most all living organisms except bacteria. Eukaryotes include organisms such as animals, plants and fungi, among others. “Nearly one-third of the proteins encoded by the human genome are transported via the COPII proteins,” he said. “Given their central role in the cell, malfunctioning COPII proteins can obviously have severe health repercussions.”
There are several somewhat rare inherited diseases that result from mutations in COPII proteins. These include chylomicron retention disease, a disorder of fat and cholesterol absorption that can impair the central nervous system; craniolenticulo sutural dysplasia, a craniofacial birth defect; and congenital dyserythropoietic anemia, a blood disorder that affects the development of red blood cells.
A second, related set of diseases results not from mutations in the COPII proteins themselves but from mutations in the proteins that the COPII proteins are supposed to transport. For example, the most common mutation that causes cystic fibrosis is one in the CFTR protein that, among other things, prevents it from interacting with the COPII proteins. Thus, the CFTR protein can never make it to the cell surface to do its job, which in turn gives rise to the often-fatal disease.
With the NIH grant, Stagg and his team of postdoctoral researchers and graduate students will study the mechanisms by which COPII proteins perform their functions.
“The primary way we go about doing this is by determining their structures,” he explained. “We use a technique called cryo-electron microscopy, or cryoEM, to analyze the structures. We are aided in these endeavors by Florida State’s newly acquired Titan Krios electron microscope, which went on line this past February.”
In 2008, Stagg was one of four FSU scientists who collaborated to bring a $2 million, NIH High-End Instrumentation grant to FSU to help the university buy the Titan Krios, a state-of-the-art, robotic electron microscope that is now being used to advance cutting-edge studies of HIV/AIDS, heart disease, hypertension and cancer, among other diseases. Using the 16-feet-tall microscope, Stagg is able to examine three-dimensional images of COPII proteins with a level of precision that few other researchers can match.
However, Stagg cautions that it is unrealistic to expect new biomedical treatments to result overnight from his team’s research.
“We are interested in the basic research right now,” he said. “It’s difficult to predict the potential medical implications that might result; basic research can be a long, laborious process that takes years to generate results. However, this sort of ground-level research is essential if breakthroughs in medicine, the sciences and engineering are to eventually occur.”
Additional information about Stagg’s research is available at www.sb.fsu.edu/~sstagg.