This 30 year Program brings together 5 Projects and 3 Cores from 2 institutions and 4 labs to explore the physiologic and pathophysiologic roles and signaling of receptors and ligands related to corticotropin releasing factor (CRF), a peptide we chemically identified at the inception of the Program. CRF is the principal neuroregulator of the hypothalamic-pituitary-adrenal (HPA) axis and acts within the brain to integrate endocrine, autonomic and behavioral responses to stressors. Many disorders including anxiety, type 2 diabetes, obesity, drug addiction and depression are associated with perturbations of the HPA axis and changes in production or sensitivity to CRF. We have chemically and biologically characterized multiple components of this system including two receptor genes (CRFR1 and CRFR2), a CRF binding protein and three urocortins (Ucn 1, 2 and 3). CRF and Ucn 1 have high affinity for CRFR1;Ucn 1 has high affinity for both receptor types;Ucn 2 and 3 are highly selective for CRFR2. This program has developed and analyzed mouse mutants that are deficient in the receptors and the three Ucns revealing unexpected roles for these peptides in the CNS, endocrine and cardiovascular systems, skeletal muscle and gastrointestinal tract. We continue our focus on stress and several projects are now emphasizing metabolism, namely control of appetite and regulation of insulin secretion and sensitivity. The 3D structures of the major binding domains of CRF receptors bound to ligands have been solved by NMR and progress has been made towards solubilizing full-length receptors. New potent and selective peptide antagonists of CRFR1 and 2 have been developed and are being used to probe the physiologic significance and the pharmacologic promise of these important signaling systems. Each of the Projects in this Program tests hypotheses relating to CRF and Ucns, and have free access to reagents and models developed within the Program. The Program comprises: Proj 1, W Vale, Project Director (PD): CRF and urocortins and their receptors;Proj 2, J Rivier, PD: Pharmacology of neuroendocrine peptides;Proj 3, S Choe/R Riek, PDs: Structural studies of the interaction between CRF G-protein coupled receptors and their ligands;Proj 4, G Koob/E Zorrilla, PDs: Behavioral significance of neuroendocrine peptides;Proj 5, P Sawchenko, PD: Anatomy of neuroendocrine peptide pathways in the brain;Core A, W Vale, Core Director (CD): Administrative;Core B, K-F Lee/ Vale, CDs: Biology;Core C, J Rivier/W Fischer, CDs: Chemistry. Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01DK026741-35
Application #
8662233
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
35
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pilbrow, Anna P; Lewis, Kathy A; Perrin, Marilyn H et al. (2016) Cardiac CRFR1 Expression Is Elevated in Human Heart Failure and Modulated by Genetic Variation and Alternative Splicing. Endocrinology 157:4865-4874
Erchegyi, Judit; Wang, Lixin; Gulyas, Jozsef et al. (2016) Characterization of Multisubstituted Corticotropin Releasing Factor (CRF) Peptide Antagonists (Astressins). J Med Chem 59:854-66
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2016) Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease. Alzheimers Dement 12:527-37
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Perrin, Marilyn H; Tan, Laura A; Vaughan, Joan M et al. (2015) Characterization of a Pachymedusa dacnicolor-Sauvagine analog as a new high-affinity radioligand for corticotropin-releasing factor receptor studies. J Pharmacol Exp Ther 353:307-17
van der Meulen, Talitha; Donaldson, Cynthia J; Cáceres, Elena et al. (2015) Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat Med 21:769-76
Radley, Jason J; Sawchenko, Paul E (2015) Evidence for involvement of a limbic paraventricular hypothalamic inhibitory network in hypothalamic-pituitary-adrenal axis adaptations to repeated stress. J Comp Neurol 523:2769-87
Mulak, Agata; Larauche, Muriel; Biraud, Mandy et al. (2015) Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice. Peptides 63:71-80
van der Meulen, Talitha; Huising, Mark O (2015) Role of transcription factors in the transdifferentiation of pancreatic islet cells. J Mol Endocrinol 54:R103-17
Jappelli, Roberto; Perrin, Marilyn H; Lewis, Kathy A et al. (2014) Expression and functional characterization of membrane-integrated mammalian corticotropin releasing factor receptors 1 and 2 in Escherichia coli. PLoS One 9:e84013

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