; We are exploring the hypothesis that the Corticotropin Releasing Factor (CRF)/urocortin family of ligands and their cognate receptors play specific and critical roles in the modulation of adaptive responses to stress and other circumstances. In previous granting periods, this Project, with collaborators throughout the Program, characterized CRF, cloned 2 CRF receptors, CRFR1 and CRFR2 and identified 3 urocortins (Ucn 1, 2 &3) and cloned CRF-BP, a bio-neutralizing binding protein. Ucn 2 and 3 precursors were deduced from DNA databases. Because their mature forms have not been identified, we will isolate and sequence the peptides from tissues and cell secretions. Our receptor studies have focused on exploring the roles of the N-terminal, first extracellular domain (ECD1) of the CRFRs, which include critical binding sites for peptide agonists and antagonists. We will continue to collaborate with Project 3, to solve the structures of additional ligand-bound ECD1 of CRF receptors by NMR and will explore means of expressing and evaluating functional full-length receptors. Mice deficient in each of the 3 urocortins developed in collaboration with Core B have been characterized. We have been instructed by the metabolic phenotypes of receptor and ligand null mice as well as by the anatomic distributions of CRFR2, Ucn 2 and Ucn 3. We proposed that Ucn 2, strongly expressed in skeletal muscle, plays a local role within that tissue to negatively regulate insulin sensitivity. Whereas, Ucn 3 found in beta cells of the pancreatic islet, enhances glucose stimulated insulin secretion. Because of possible interest in increasing insulin sensitivity by selectively blocking Ucn 2, we are developing mutant CRF-BPs that bind and neutralize Ucn 2 but display minimal affinities for CRF, Ucn 1 and Ucn 3, thereby avoiding suppression of glucocorticoid production and possible untoward effects on islet, heart and other tissues. We have also explored the role of CRF and CRFR1 in the islet and found this receptor/ligand system to also enhance glucose-mediated insulin secretion. We propose to fully define the distributions of ligands and receptors of the CRF network within the islet and to explore the regulation of the CRFR1 and CRFR2 components and cross-talk between the two receptor systems. Finally, we will examine this system in models of obesity. Our goal is to understand the physiologic context of the CRF/urocortin network and to reveal potential means of exploiting this information for the management of human stress-related and metabolic diseases.

Public Health Relevance

; The CRF/urocortin network mediates endocrine, autonomic and behavioral responses to stress and is perturbed in various mood and metabolic disorders. Clinical trials of native peptides and their antagonists are underway for the management of several indications including depression, anxiety, acute congestive heart failure and irritable bowel syndrome. Recent findings of possible roles of this family in insulin secretion and muscle insulin sensitivity reveal potential applications in metabolic disease including type 2 diabetes.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01DK026741-35
Application #
8662234
Study Section
Special Emphasis Panel (ZDK1)
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
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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
van der Meulen, Talitha; Huising, Mark O (2014) Maturation of stem cell-derived beta-cells guided by the expression of urocortin 3. Rev Diabet Stud 11:115-32
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Benner, Christopher; van der Meulen, Talitha; Cacéres, Elena et al. (2014) The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15:620
Szabadfi, K; Kiss, P; Reglodi, D et al. (2014) Urocortin 2 treatment is protective in excitotoxic retinal degeneration. Acta Physiol Hung 101:67-76
Koob, George F; Buck, Cara L; Cohen, Ami et al. (2014) Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B:370-82
Logrip, Marian L; Zorrilla, Eric P (2014) Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. Front Integr Neurosci 8:30
Logrip, Marian L; Vendruscolo, Leandro F; Schlosburg, Joel E et al. (2014) Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology 39:1722-31

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