Objective The obesity epidemic is a pressing problem, resulting in diverse metabolic and psychological disorders.Identification of genes whose disruption causes obesity in rodents has led to rapid progress in understanding the signalling pathways responsible for the regulation of body weight in mammals, and an increasing number of severely obese humans have been found to carry mutations in those same genes.The fat-derived hormone leptin and the neurotrophin brain-derived neurotrophic factor (BDNF) are key players in the brain circuitry regulating energy homeostasis, and genetic disruption of their receptors, the leptin receptor (Ob-R) and the neurotrophin receptor Tropomyosin-related kinase (TrkB), causes hyperphagia and obesity in rodents and humans.Only one pathogenic mutation has been described to date in human for both TrkB and Ob-R and the data strongly indicate causality. Recently, the host laboratory has identified several novel mutations in TrkB and Ob-R in severely obese children.To determine whether these mutations result in non-functional receptors and thus are the causes of obesity in the affected individuals, we propose to make constructs of the mutant receptors and transfect them in appropriate cell lines.We will use state-of-the art methodologies for immunohistochemistry, confocal microscopy, Western blotting and receptor ligand binding assays to characterize the functionality of the presumed pathogenic variants.This proposal is part of a multidisciplinary project that will combine human genetics, human pathophysiology and functional genomics to explore the contribution of TrkB and Ob-R mutations to the development of severe childhood onset obesity.Moreover, the results of these experiments will provide new knowledge on the role of these signalling pathways in the regulation of body weight, and possibly lead to identification of new targets for the treatment of obesity. Fields of science medical and health sciencesbasic medicinephysiologypathophysiologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicinemedical geneticsmedical and health sciencesbasic medicinephysiologyhomeostasismedical and health scienceshealth sciencesnutritionobesity Keywords biochemistry cell biology genetics leptin receptor (Ob-R) obesity tropomyosin-related kinase receptor (TrkB) Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.3 - Marie Curie Incoming International Fellowships (IIF) Call for proposal FP6-2005-MOBILITY-7 See other projects for this call Funding Scheme IIF - Marie Curie actions-Incoming International Fellowships Coordinator THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE EU contribution No data Address The Old Schools Trinity Lane CAMBRIDGE United Kingdom See on map Links Website Opens in new window Total cost No data
