Regulation and Function of Urocortins and their Receptors
Principal Investigator: Aditi Bhargava
Abstract: PROJECT SUMMARY/ABSTRACT The corticotropin-releasing factor (CRF) family of neuropeptides (CRF and urocortins [Ucn] 1-3) and their receptors (CRFR1, CRFR2) are essential mediators of stress in the central nervous system. Therefore a systemic inhibition of their function is not an attractive therapeutic model. Components of this peptide/receptor family are prominently expressed within the intestine, where their local functions remain to be defined. Our preliminary data from CRFR2 heterozygous mice suggests that perturbation of the CRFR2 system renders the mice more susceptible to sudden stress and immune challenges. Our results suggest that new treatments for intestinal inflammatory diseases may require either antagonists or agonists of CRF receptors, depending upon the affected intestinal region and the type of inflammatory disease. A striking feature we observed during colitis was reciprocal changes in mRNA and protein levels of Ucn ligands and their receptors. These differential changes can alter Ucn-induced trafficking of receptors from and to the plasma membrane. However, the molecular mechanisms of this divergent trafficking to recycling or degradatory pathways remain unexplored. Thus, our hypothesis is that Ucn isoforms, differentially signaling through CRF receptors, govern intestinal inflammation at the molecular, cellular and organ levels. The aims of this proposal are to: Specific Aim 1. To define the systemic role of the Ucn/CRFR system in intestinal inflammation. We will use pharmacological and genetic approaches to define the systemic role of the Ucn/CRFR system in intestinal inflammation. We will determine if CRFR2 knockout and heterozygous mice exhibit differential sensitivity to inflammation and agonist treatment as compared with their wild type littermates. We will determine alterations in colitis severity by measuring changes in body weight gain, mortality, histological damage, and fluid leak. Specific Aim 2. To define the contributions of colon-specific Ucns and CRFRs in intestinal inflammation using RNA interference (RNAi). To determine the colon-specific role of the Ucn/CRFR system, we will establish the use RNAi to knockdown expression of Ucns and CRFR2 locally in the colon. We will determine the spatial and temporal effects of RNAi in the colon, and assess whether colon-specific knockdown of Ucns and CRFRs is sufficient to ameliorate or exacerbate colitis, using end points defined in Specific Aim 1. Specific Aim 3. To define the mechanism and function of Ucn1-induced trafficking of CRFR1. We will examine the influence of Ucn1 stimulation on the subcellular localization of CRFR1 using confocal microscopy and immunofluorescence. We will explore the ability of the adaptor/scaffolding proteins ([unreadable]-arrestins and dynamin) to desensitize and resensitize CRFRs. We will assess Ucn1 regulation of CRFR1 activity by measuring Ucn1-stimulated intracellular Ca2+ mobilization. Thus, manipulation of the urocortins and their receptors provides an effective starting point for understanding their GI functions, which could contribute to the development of new treatments for inflammatory bowel disease.
Funding Period: 2009-04-01 - 2014-03-31
more information: NIH RePORT
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Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA
Endocrinology 150:5428-37. 2009..Ucn1's effect on L(p) is partially mediated by the CRH-R(2) receptor and acts independently of the c-JUN N-terminal kinase signal transduction pathway...
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Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA
Mol Med 19:212-22. 2013..Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics...
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Department of Surgery, University of California, San Francisco, CA 94143 0660, USA
Proc Natl Acad Sci U S A 110:731-6. 2013..difficile infection...
- Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survivalHyung Joon Kim
Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul 110 749, Korea
J Cell Biol 199:1145-58. 2012..Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca(2+) signaling in osteoclasts...
- Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese miceMaria Pini
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America
PLoS ONE 7:e40944. 2012..However, RGZ worsens selective parameters of AP severity in LFD mice...
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Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, San Francisco, CA 94143 0660, United States
Peptides 35:202-11. 2012..Thus, CGRP and IMD appear to be released locally, where they can mediate their effect on their receptors regulating diverse functions such as inflammation, pain and motility...
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Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
J Leukoc Biol 91:957-66. 2012....
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Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California, San Francisco, San Francisco, California 94143, USA
Mol Endocrinol 26:681-95. 2012....
- Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adultsLiansheng Liu
Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, United States of America
PLoS ONE 6:e19498. 2011..We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them...
- Urocortin 1 modulates immunosignaling in a rat model of colitis via corticotropin-releasing factor receptor 2Jen Chang
Dept of Surgery, Univ of California, San Francisco, 94143 0660, USA
Am J Physiol Gastrointest Liver Physiol 300:G884-94. 2011..Thus we conclude that local CRF(2) and pERK1/2 activation is pivotal for macroscopic spread of colitis and resolution of edema. Elimination of CRF(2), but not CRF(1), results in uncoordinated immune and pERK1/2 signaling responses...
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Department of Physiology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
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- Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidneyAlan C Pao
Div of Nephrology, Dept of Medicine, Stanford Univ, 780 Welch Rd, Suite 106, Palo Alto, CA 94304, USA
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- c-Jun NH2-terminal kinase-2 mediates osmotic stress-induced tight junction disruption in the intestinal epitheliumG Samak
Department of Physiology, University of Tennessee Health Science Center, Memphis, 38163, USA
Am J Physiol Gastrointest Liver Physiol 299:G572-84. 2010..These results reveal the role of JNK2 in the mechanism of osmotic stress-induced TJ disruption in the intestinal epithelium...
- Urocortin 3 expression at baseline and during inflammation in the colon: corticotropin releasing factor receptors cross-talkShilpi Mahajan
Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
Peptides 54:58-66. 2014..Thus, our results suggest that a balanced and coordinated expression of CRF receptors is required for proper regulation of Ucn3 at baseline and during inflammation. ..