JUPITER, Fla.—The Scripps Research Institute hasbeen awarded a $1.3 million grant by the National Institutes of Health (NIH) todevelop a series of tests at its Florida campus to help explore the potentialof a protein that has emerged as a highly attractive target for the treatmentof obesity and Type 2 diabetes.
Patricia McDonald, an associate scientificdirector in the Translational Research Institute at Scripps Florida and anassistant professor in the Department of Molecular Therapeutics, is theprincipal investigator for the three-year project funded by the NIH's NationalInstitute of Diabetes and Digestive and Kidney Diseases (NIDDK).
"Because obesity and diabetes are two of the mostserious health problems facing us, the need for novel treatments has never beengreater," McDonald said. "Some recent studies in animal models have shown thatactivating the G protein-coupled receptor GPR119 improves glucose homeostasisor balance, while positively affecting both food intake and weight gain. Thisfunding will help us design new assays that will explore the overall potentialof GPR119 – and may one day lead to more effective treatments."
G protein-coupled receptors (GPCRs) are thelargest and most diverse protein family in the human genome. They transduce orconvert extracellular stimuli including neurotransmitters, light, hormones,lipids, and peptides into intracellular signals through a number of signalingpathways. Approximately one-third, and perhaps as many as half, of currentlymarketed drugs are designed to target these receptors.
GPR119 is expressed predominantly in the pancreasand gut of humans and rodents and in the rat brain. When activated, thereceptor promotes secretion of a specific hormone, called Glucagon-LikePeptide-1 (GLP-1), in the intestines, which in turn increases insulin secretionfrom the pancreas; both are key components in regulating the balance of glucosein the body. Although some modulators of GPR119 have been discovered, they donot necessarily mimic the receptor's natural ligand and have thus turned out tobe mostly unsuitable for use in studying the receptor's biology and function.
"In terms of treating metabolic disease throughmodulation of GPCRs," McDonald said, "an obvious candidate such as the GLP-1receptor has been a historically difficult target to track with small molecules,but GPR119 is much more amenable to modulation, plus it also regulates theGLP-1 axis, which is what makes it such a potentially valuable target indiabetes and obesity. We chose this particular receptor for those reasons—andthe fact that it's being studied extensively by the pharmaceutical industry."
McDonald hopes that once the new assays aredeveloped, and molecular probes created, the process will lead to theidentification of small molecule compounds that can be used therapeutically.The probes themselves might even have potential in this regard.
"We'll be studying these probes to see if theyhave any drug-like properties, particularly if they show any significantactivity against the GPR119 receptor," she said. "The obvious goal would be toimprove a probe's therapeutic qualities—oral bioavailability, for example—whilekeeping its high level of activity, a process that can be a lot more difficultthan it sounds."
