Corticotropin-releasing factor (CRF) and urocortin (Ucn) 1 interact with two Gs coupled CRF1 and CRF2 receptors. Recently, new CRF-related peptides, Ucn 2 and Ucn 3 were discovered as selective CRF2 agonists. Activation of CRF1 signaling pathway in the brain reproduces the overall endocrine and behavioral responses to stress. In the last granting period, we established that activation of brain CRF1 signaling plays also a prominent role in stress-related stimulation of colonic motor function and visceral hyperalgesia in rodents. The overall objective of the proposal, based on preliminary data, is to establish that activation of brain CRF2 curtails CRF1-mediated stress-related stimulation of colonic motility (aim 1) and hyperalgesia (aim 2) while both CRF1 and CRF2 receptors are recruited to inhibit gastric motor function in a stressor specific manner (aim 3). Colonic motility and visceral hypersensitity will be monitored using novel non-invasive methods that we developed in conscious rats.
Aims will be achieved using selective CRF1 and CRF2 agonists and antagonists. The paraventricular nucleus of the hypothalamus and Barrington-sacral spinal cord projections to the sacral parasympathetic nucleus that influence colonic myenteric neurons will be targeted as sites of receptor interactions and pathways to influence colonic motility. The locus coeruleus activated by colorectal distention through CRF1 receptor and expressing Ucn 2 will be investigated as a site to modulate visceral hyperalgesia. Role and brain sites of action will be assessed pharmacologically and using laser capture microdissection combined with quantitative PCR to reveal stress-related alterations in gene expression pattern of Ucn 2, CRF1, CRF2 and novel functional CRF1a2 variants that we recently isolated from the rat brain. These studies will provide accurate expression of CRF ligands and cognate receptors and their variants and regulation at brain sites responsive to stress not achieved before. It will provide new insight to the role of brain CRF2 and CRF1 signaling and their interactions in stress-related alterations of gut motor function and visceral pain induced by stress. The preclinical studies may have implications in functional bowel diseases fo which mounting evidence involve the brain-gut axis.

Public Health Relevance

Brain peptide corticotropin-releasing factor (CRF) signaling pathways which are involved in stress response can initiate and aggravate functional bowel diseases, such as irritable bowel syndrome, dyspepsia and cyclic vomiting syndrome. We will study the mechanisms through which CRF, its related peptides acting on two distinct receptors in the brain, exert differential or convergent effects to influence gut motor function and hypersensitivity of the colon. These studies have the potential to underpin molecular mechanisms of stress-related gut diseases leading to new treatment targeting these stress pathways.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Serrano, Jose
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Yuan, Pu-Qing; Wu, S Vincent; Pothoulakis, Charalabos et al. (2016) Urocortins and CRF receptor type 2 variants in the male rat colon: gene expression and regulation by endotoxin and anti-inflammatory effect. Am J Physiol Gastrointest Liver Physiol 310:G387-98
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
Taché, Yvette; Adelson, David; Yang, Hong (2014) TRH/TRH-R1 receptor signaling in the brain medulla as a pathway of vagally mediated gut responses during the cephalic phase. Curr Pharm Des 20:2725-30
Goebel-Stengel, Miriam; Stengel, Andreas; Wang, Lixin et al. (2014) Orexigenic response to tail pinch: role of brain NPY(1) and corticotropin releasing factor receptors. Am J Physiol Regul Integr Comp Physiol 306:R164-74
Karasawa, Hiroshi; Yakabi, Seiichi; Wang, Lixin et al. (2014) Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of the stable somatostatin pan-agonist, ODT8-SST in rats. Neurosci Lett 576:88-92
Yakabi, Koji; Harada, Yumi; Takayama, Kiyoshige et al. (2014) Peripheral ?2-?1 adrenergic interactions mediate the ghrelin response to brain urocortin 1 in rats. Psychoneuroendocrinology 50:300-10
Stengel, Andreas; Taché, Yvette (2014) Brain peptides and the modulation of postoperative gastric ileus. Curr Opin Pharmacol 19:31-7
Stengel, A; Taché, Y (2013) Role of NUCB2/Nesfatin-1 in the hypothalamic control of energy homeostasis. Horm Metab Res 45:975-9
Goebel-Stengel, Miriam; Wang, Lixin (2013) Central and peripheral expression and distribution of NUCB2/nesfatin-1. Curr Pharm Des 19:6935-40
Stengel, Andreas; Rivier, Jean; Taché, Yvette (2013) Central actions of somatostatin-28 and oligosomatostatin agonists to prevent components of the endocrine, autonomic and visceral responses to stress through interaction with different somatostatin receptor subtypes. Curr Pharm Des 19:98-105

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