Overcoming the severe drive to overeat and obesity that provides the greatest threat to life expectancy and life quality is of upmost and crucial importance for PWS individuals and families. Despite advances in understanding the genetic causes of PWS and the establishment of different mouse models that mimic some clinical components, the underlying cause of PWS is not known and no animal model exists that models the overeating and obesity of PWS. Consequently, in this project we propose to generate a physiologically similar animal model of PWS using the miniature pig. The successful outcome of this work will, for the first time, provide an animal model in which clinical, dietary, pathological, and genetic studies can lead to an understanding of exactly how the PWS genes control how much we eat and how that energy is utilized or stored and results in obesity with increased fat and decreased muscle mass. Having a pig model of severe hyperphagia and obesity in PWS will also allow development and future testing of therapeutic approaches (whether dietary, surgical, pharmacological, genetic, stem cell, and/or neural transplantation). The proposed research to generate an optimal animal model of PWS spans all eight areas of most interest to FPWR, including 1) generation of a relevant animal model for all aspects of PWS, 2) clinical, pathological, and molecular studies of the basis of hyperphagia and obesity, 3) studies on the hypothalamus and other brain areas in PWS-model piglets, 4) studies on muscular hypotonia, hormone abnormalities, sleep, sleep apnea, scoliosis, osteoporosis and other clinical aspects of the PWS-model pigs will be guided by existing studies in all these areas in the pig, 5) the ability to obtain critical tissues such as the brain, muscle and adipose tissue for studies of the PWS-region genes and imprinting, 6) development of a resource for the entire biomedical research community, as well as an animal model that can be used for studies of 7) behavior and 8) learning disabilities based on comparison to ongoing, new studies of normal pig behavior. Consequently, the proposed project can provide an enormous breakthrough for PWS research.