Dr. Sweeney has shown that the melanocortin 3 receptor (MC3R) is important in regulating food intake and has developed an antagonist of MC3R that inhibits feeding. Here he will test whether inhibition of MC3R decreases food intake in a mouse model of PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Prader Willi Syndrome (PWS) is associated with insatiable hunger, accompanied by an increased risk for developing obesity and metabolic syndrome. This hunger greatly decreases the quality of life of Prader Willi patients and family members, and represents a major unmet medical need. Previous studies from our laboratory and others have determined that hypothalamic neurons expressing agouti-related protein (AgRP) are activated in response to hunger. Pre-clinical and clinical evidence suggests that these neurons are over-activated in Prader-Willi patients. In aim 1 of this proposal we will utilize a novel mouse model to determine how Prader Willi Syndrome effects the activity patterns of AgRP neurons in awake behaving mice (aim 1). Recently, our laboratory determined that the melanocortin-3-receptor (MC3R) is expressed in nearly 100% of AgRP neurons, and that inhibition of this receptor blocks the transmission of hunger signals from the AgRP neurons. In aim 2 we will test the hypothesis that pharmacological inhibition of MC3R prevents hyperphagia in Prader Willi Syndrome. Together, these 2 aims will provide mechanistic insights into the cause of hyperphagia in Prader Willi Syndrome and test a novel pre-clinical candidate for preventing hyperphagia in PWS. Findings from these studies will provide the required preliminary data to apply for larger scale research grants (NIH R01 and equivalent) focused on determining the mechanism(s) for altered AgRP activity in PWS, while also providing the necessary rationale to advance MC3R antagonist compounds towards clinical trials for hyperphagia in Prader Willi Syndrome.
Patrick Sweeney, Ph.D.
University of Illinois
Patrick Sweeney, PhD