James Hougland
Top-notch ideas drive today’s knowledge-based world. James Hougland has one, and he has been awarded a “Best Idea Grant (BIG)” from the Foundation for Prader-Willi Research (FPWR) to support his research. Hougland, an assistant professor of chemistry in The College of Arts and Sciences, is working in collaboration with a medicinal chemist at Purdue University on the project, which is supported by $108,000 over one year.
Hougland’s effort will take aim at a major symptom of Prader-Willi syndrome (PWS). The condition is a genetic disorder that occurs in approximately one out of every 15,000 births. PWS affects males and females with equal frequency and touches all races and ethnicities. It is recognized as the most common genetic cause of life-threatening childhood obesity.
“Obesity and insatiable appetite—hyperphagia—are among the most serious symptoms experienced by PWS patients,” says Hougland. “While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in PWS.”
Patients with PWS have elevated levels of ghrelin in their bloodstreams, suggesting that the voracious appetite that accompanies the disease may arise from overstimulation of ghrelin-mediated signaling. Based on this hypothesis, Hougland believes that novel therapeutic agents targeting ghrelin have potential as treatment options for PWS-associated hyperphagia.
But first, he has to understand the enzymes that are involved in ghrelin signaling. “Ghrelin O-acyltransferase (GOAT), an enzyme that modifies ghrelin, offers an excellent target for specifically blocking ghrelin activity. GOAT attaches a fatty acid to ghrelin, with only the modified form of ghrelin demonstrated to activate hunger signaling. This fatty acid modification is unique to ghrelin among appetite-regulating hormones,” says Hougland.
Designing inhibitors for GOAT is difficult because very little is known about how GOAT binds ghrelin and catalyzes ghrelin modification. To break this bottleneck in developing GOAT inhibitors, Hougland’s research will determine the interactions between ghrelin and GOAT that are required for GOAT-catalyzed ghrelin modification.
“We will then synthesize molecules that block these interactions and evaluate them as potential GOAT inhibitors,” he says. “By gathering fundamental knowledge about how GOAT recognizes and modifies the appetite-stimulating hormone ghrelin, we will lay the foundation for creating a new class of therapeutics for treating hyperphagia in patients with PWS.”
The research may have applications beyond PWS; for example, there may be connections between ghrelin signaling and diabetes. “If we can control and modify ghrelin signaling through GOAT inhibitors, it may provide a new avenue for treating diabetes,” Hougland says.
The interdisciplinary research by Hougland and his team—five graduate students, one undergraduate and a lab manager—draws on techniques from organic chemistry, biochemistry and molecular and cell biology. The team is already breaking ground in the lab—it developed a new, fluorescence-based assay that accelerates the ability to study the enzyme, and makes it easier to study specific aspects of ghrelin recognition. “Instead of having to express proteins in bacteria, we synthesize the substrates we want,” Hougland says. “This approach is much faster, and also allows us to ask a wider range of questions.”
Speed matters. Hougland initially got interested in working on ghrelin and GOAT because ghrelin octanoylation is a unique protein modification involving interesting chemistry. As he reviewed the literature, he began to see the number of diseases and syndromes where ghrelin may play a role.
“I think there is an emphasis at the University that, if there’s work worth doing that could have impact beyond the academy, if we can do things in the laboratory that are going to help the world in general, the idea is to get that work out there as quickly as possible,” he says.
Parents and loved ones of children suffering from Prader-Willi couldn’t agree more. Hougland’s grant proposal was reviewed not only by scientific peers but by advocates, including parents. One parent advocate spoke of how, while Prader-Willi patients have many challenges to overcome and live with, the symptom they feared the most was hyperphagia. Insatiable appetite leads to obesity, an immediate health problem, and long-term risks like cardiovascular disease.
“Prader-Willi is a genetic disease; even if we can develop a perfect GOAT inhibitor, we won’t cure it with our work,” Hougland says. “But if we can alleviate the insatiable appetite, and suppress the obesity that comes with the syndrome, it’s a way to eliminate a number of health risks for those patients.”
