The corticotropin-releasing factor (CRF) family of signaling molecules plays important and interactive roles in effecting integrated endocrine, autonomic and affective/behavioral responses to stress. It includes four ligands (CRF and urocortin (Ucn) 1-3) that signal though either or both of two G protein-coupled receptors (CRFRl and CRFR2). An interconnected network of CNS cell groups, termed the central autonomic system (CAS), comprises sensitive sites of stress-related CRF/Ucn action, but neither the bases for CRF ligandreceptor signaling within them, nor the circuitry that provides for documented interactions between CRFR1 - and R2-dependent mechanisms in sculpting individual modes of stress adaptation, are well understood. We will work with other components of the Program to validate immunologic and molecular genetic tools with which to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. Evidence that functional manifestations of the ligand-receptor "mismatch" may be accommodated by presynaptic CRFR expression, novel endogenous Ucn forms and/or systemic effects of centrally administered peptides will be pursued. A second major goal is to define the extended circuitries that provide for CRFR interplay in regulating stress-induced activation of (1) hypothalamic neurons that govern activation of the pituitary-adrenal axis, and (2) cell groups in the amygdala that mediate affective behaviors related to anxiety. Transgenic CRFR reporter mice will be employed to identify stress-sensitive, receptor-bearing intrinsic and extrinsic cell groups potentially involved in these functions. Combined histochemical and axonal transport methods will then be used to progressively unravel candidate circuitries by which CRFR1 and -R2 mechanisms may interact to shape the endpoints of interest and the disposition of CRFR ligands within them. Finally, site-specific, conditional gene targeting methods will be used to test the functional involvement of key nodes of the implicated circuits in stress-induced pituitary-adrenal hormone secretion and behavioral measures of anxiety. The results are expected to provide a systems level perspective on the role of the central CRF system in critical facets of the stress response, and a stringent test of the integrative capacities attributed to this system in stress adaptation.

Public Health Relevance

Aspects of the central CRF system have been implicated as potential targets for therapeutic intervention in obesity, autoimmune disease, a range of affective disorders and age-related neurodegenerative disease. Small molecule CRFR1 antagonists are in advanced clinical trials for the treatment of depression and other anxiety-related disorders. In providing a functional neuroanatomical context for CRF signaling in key sites of stress-related peptide action, our results are expected to inform these and other potential applications.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01DK026741-35
Application #
8662237
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
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
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52
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

Showing the most recent 10 out of 380 publications