A team of Florida State University researchers has received a $1.19 million grant from the National Institutes of Health to use molecular archaeology to investigate the evolution of critical cellular processes that often go awry in human diseases, including diabetes.
Brian Miller, professor of Chemistry and Biochemistry, and Carl Whittington, assistant in research in the Department of Biological Science, have teamed up to take a cross-disciplinary approach to understand how critical protein regulatory mechanisms arose in cells over evolutionary history.
“The results of our investigations are expected to provide new insight into the evolutionary origins of diseases such as hyperinsulinemia and diabetes, which are caused by incorrect regulation of glucokinase activity,” Miller said.
Miller and Whittington will examine the history of glucokinase, a type of enzymatic protein that serves as the body’s primary glucose sensor as it relays signals in the pancreas and liver, triggering glycogen synthesis and insulin release. When that function is impaired, a person often suffers from diabetes or hyperinsulinemia.
“The goal of this project is to resurrect extinct proteins – molecular fossils – in the lab and study their biochemical and biophysical properties to understand how evolution tailored their functions for optimal performance,” Miller said.
The starting point for retracing the evolutionary history of glucokinase will be resurrecting a 640 million-year-old ancestor in the lab. Using phylogenetics, the researchers will build a family tree of glucokinases from humans and other modern species and determine the genetic sequence of the enzyme in an extinct, ancestral organism.
This ancient version corresponds to the enzyme likely present in the last common ancestor of modern chordates – the group containing humans and other vertebrates, lancelets and sea squirts. The process will yield a detailed accounting of all the mutations that occurred in glucokinase over the last several hundred million years.
“We want to understand where in the timeline functionally important changes occurred,” Whittington said. “Then we will apply our suite of experimental tools, including functional and structural characterization techniques, to analyze the changes. We’re hoping to gain a molecular-level understanding of several types of protein regulation mechanisms through this process.”
Because of the broad range of techniques used in the project, a group of multidisciplinary scientists is required. In addition to Miller and Whittington, FSU Professor of Biological Science Darin Rokyta, an expert in molecular evolution, as well as graduate students Seyedehshirin Kamalaldinezabadi and Joshua Santiago are involved on the project.