The corticotropin-releasing factor (CRF) family of signaling molecules comprises four ligands (CRF, and urocortins (Ucns) 1-3), two receptors (CRFR1 and -R2) and a binding protein (CRFBP). This family is thought to play critical and interactive roles in the integration of endocrine, autonomic and behavioral responses to stress. An interconnected network of brain structures, termed the central autonomic system (CAS), harbors sensitive sites of stress-related CRF/Ucn action, but its components are generally lacking or impoverished in relevant ligand and/or receptor expression. Our goal is to clarify the functional anatomical organization that provides for generalized stress-induced CAS activation, by ascertaining the disposition and role of specific signaling molecules in specific locations that provide for recruitment of this circuitry in a range of challenge paradigms. Immunolocalization methods will be used at the light and electron microscopic levels to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. We will work with other components of the program to pursue evidence of a novel CRFR enriched in CAS, and if successful, determine its distribution and role in CAS circuitry. Histochemical and anatomical methods will be used to identify molecular targets and sites within the CAS at which CRFR1 and R2 mechanisms interact to sculpt stress responses, and to identify the underlying circuitry. Pharmacologic manipulations in genetically manipulated mouse models will be used to pursue indications of an unexpected role for the CRFBP in signaling in the CAS. Anatomical and functional studies will seek to provide a context for a newly discovered soluble CRFR2 variant. Finally, we will explore a range of possible explanations for the failure of recently discovered CRFR2-selective ligands, Ucn 2 and 3, to activate sites of cognate receptor expression. We will compare the extent to which Ucn 1, 2 and 3-expressing cell groups may be differentially responsive to a range of challenge paradigms, and employ null mutant lines to probe the roles of each peptide system in CAS responses to stress. The CMS systems under scrutiny here play essential physiologic roles in stress adaptation, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age-related deficits in learning and memory, and have been implicated in the etiology of a range of affective disorders, including anorexia nervosa and major depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK026741-29
Application #
7628122
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
29
Fiscal Year
2008
Total Cost
$219,045
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Spierling, Samantha R; Mattock, Maegan; Zorrilla, Eric P (2017) Modeling hypohedonia following repeated social defeat: Individual vulnerability and dopaminergic involvement. Physiol Behav 177:99-106
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
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
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
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2015) Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model. J Alzheimers Dis 45:639-50
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
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
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

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