Two Experts. One Protein. And the Mission That Binds Them
The CDI funding brings together two Washington University School of Medicine researchers and attending physicians at St. Louis Children’s Hospital, Paul Hruz, MD, PhD, pediatrics; and Brian DeBosch, MD, PhD, pediatrics. They share an interest in GLUT8, one of several proteins whose job is to transport glucose, fructose and other sugars into cells throughout the body.
Dr. Hruz, along with colleagues in his lab, has been studying glucose transporters for the past 20 years, and he has had a long-standing interest in how diseases can arise from structural abnormalities in these proteins. With previous CDI funding, he collaborated with Katherine Henzler-Wildman, PhD, a former Washington University School of Medicine associate professor of biochemistry and molecular biophysics who is now at the University of Wisconsin, to use high-resolution nuclear magnetic resonance to analyze the structure of another protein, GLUT4, and how it is able to efficiently transport glucose into cells.
As a post-doctoral fellow, Dr. DeBosch was part of an effort to determine the role GLUT8 plays in regulating whole body metabolism. Through this work, he and his colleagues found that mice lacking this transporter do not develop pre-diabetes.
Dr. DeBosch and Dr. Hruz’s new study aspires to find a drug that can selectively block GLUT8’s ability to transport glucose into the liver. They will use the technique Drs. Hruz and Henzler-Wildman developed to analyze the structure of GLUT8 and help them determine the protein’s unique vulnerabilities.
“This study will broaden our general understanding of glucose transport proteins and will build on the work previously funded by the CDI,” Dr. Hruz says.
“And,” Dr. DeBosch adds, “this interdisciplinary study allows us to combine my expertise in fatty liver disease with Paul’s decades of experience in structural biology to do work no one else in the world is doing, with tools and knowledge no one else is employing. It’s really exciting.”
Because there is such a strong connection between insulin-resistant diabetes and fatty liver disease, the Hruz-DeBosch team began by looking into diabetes drugs that work by binding to glucose transporters. They will put these compounds in mice and observe what effect, if any, they have on the proteins. Compounds shown to affect GLUT8 will be further tested to see how they can be made stronger and more selective to GLUT8.
Their findings can be used as a springboard for NIH funding and/or a partnership with a pharmaceutical company.
“We are physician-scientists and that’s our dream to make a drug discovery and bring it to the bedside to help scores of children,” Dr. DeBosch says. “The CDI has put us on a solid path to do just that.”