Corticotropin releasing factor (CRF) is known to be a major regulator in the response to stress. The recent cloning and characterization of urocortin (UCN), a CRF-like peptide, has opened a new direction in the study of the stress response and the HPGA axis. Although the exact role or function of UCN has not yet been determined, it has been reported that this peptide has a higher affinity for the CRF2 receptor (CRFR2) than does CRF and is hypothesized to be the endogenous ligand for this receptor. Additionally, it has recently been discovered that UCN has suppressive effects on appetite. Since the CRFR2 localizes to the ventromedial hypothalamus (VMH), the center of appetite regulation in the brain, and since CRFR2 is thought to be the endogenous receptor for UCN, it is our goal to generate mice carrying a null mutation for the CRFR2 in order to examine the role of this receptor in appetite suppression in response to UCN treatment. We propose to produce and characterize mice carrying a null mutation for the CRFR2 and to evaluate the physiological effect of this mutation on appetite and in the stress response under normal and stressed conditions following UCN treatment. The general phenotype of these animals will be determined by their developmental capacity and by histological analyses. Additionally, we propose to examine the effects of components of the stress response on CRFR2 gene expression by in situ hybridization following physical stress as well as exogenous application of CRF and UCN. Increased understanding of the CRF system and its components is critical to further benefits in the development of new clinical and therapeutic applications in the treatment of diseases related to eating disorders and stress.
|Bale, Tracy L; Picetti, Roberto; Contarino, Angelo et al. (2002) Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 22:193-9|
|Bale, T L; Contarino, A; Smith, G W et al. (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24:410-4|