Stress hormones (Corticotropin-releasing factor or CRF and its receptors) are the first responders that mediate the classic “fight” or “flight” response via activation of the hypothalamic-adrenal-pituitary axis. Animal models of depression, anxiety and functional bowel diseases have shown that CRF and CRF receptor antagonism ameliorate many of these disease symptoms. While the underlying cause of these and other stress-related diseases involves a complex interaction between genes and environment, we hypothesize that dysregulation of components of the CRF system tips the critical balance between pro-and anti-inflammatory signaling responses, and contribute to the diseased state.
Gut-brain Interactions in Stress-related Disorders
Traumatic and stressful events are common experiences of our daily lives. Not surprisingly, the incidences of stress-related illnesses such as mood disorders, PTSD, functional dyspepsia, and IBD have surged in the past few decades. Gastrointestinal manifestations of bowel diseases include abdominal pain, diarrhea, and/or constipation, and rectal bleeding. This project focuses on delineating the mechanisms of CRF/Ucn signaling in the gut, and how these mechanisms contribute both to the normal function of the enteric and central nervous system and to stress-induced pathophysiology at the molecular, tissue and organ levels. Our recent work is trying to understand how this CRF system responds differently during stress and inflammation, in a sex-specific manner.
Mechanisms of CRF- and Ucn-stimulated Trafficking and Signaling of CRF Receptors
CRF and Ucns are potent inflammatory mediators that act via two known GPCR receptors. Activation of CRF receptor 1 (CRF1) during inflammation can result in distinct, and often times opposite functional effects, however it is unclear whether different CRF1 agonists bring about this paradoxical effect on inflammation, or other subcellular factors determine the fate of activated CRF1 function. We are investigating the role of endothelin-converting enzyme-1 (ECE-1) in promoting CRF-R recycling and resensitization.
Role of Urocortins and their receptors in Pancreatitis
Patients with IBD develop extraintestinal complication of pancreatitis, likely because of inflammatory mechanisms common between these two diseases. Our pilot data shows that under normal conditions, Ucn1 is expressed in islet cells of the pancreas alone. Interestingly, during pancreatitis, acinar cells show de novo expression of Ucn1, but the role of Ucn1 and its receptor in pancreatic inflammation remain unexplored. Furthermore, CRF2 knockout mice show secretion defects and alterations in endoplasmic ultrastructure when examined under electron microscope. Urocortin1 (Ucn1) plays a pivotal, though paradoxical role in causing intestinal inflammation. Exploring shared pathways that contribute to progression of these illnesses will offer highly relevant therapeutic and diagnostic approaches.
RNA Interference (RNAi)-Mediated Gene Therapy
We have successfully developed use of RNAi in freely moving adult rodents to manipulate expression of the CRF family of neuropeptides in neuronal populations in a reversible fashion (Brain Res Protoc, 2004, PNAS 2005). RNAi for silencing gene expression in vivo is an extremely powerful tool in teasing out gene function and neural circuitry. We now hope to use novel fluorescent and magnetic nanoparticles conjugated to dsRNA for non-invasive delivery of RNAi for therapeutic treatment for pain and inflammatory diseases. In addition, we are developing novel methods to deliver RNAi to specific pain neurons. A pilot T1 Catalyst award from UCSF funded part of this work.
1. Bhargava† A, Chen† S-Y, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone G, Verrey, F, and Pearce D. (1999) Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc. Natl. Acad. Sci., 96: 2514-2519. (†: equal contribution by two authors).
2. Bhargava A, Meijer OC, Dallman MF, and Pearce D. (2000) Plasma Membrane Calcium Pump Isoform 1 Gene Expression is Repressed by Corticosterone and Stress in Rat Hippocampus. J. Neuroscience. 20(9):3129-3138.
3. Bhargava A, Dallman MF, Pearce D and Choi SJ. (2004). Long double-stranded RNA mediated interference as a tool to achieve site-specific silencing of hypothalamic neuropeptides. Brain Res Protoc. 13 (2): 115-25.
4. la Fleur SF, Wick EC, Idumalla PS, Grady EF and Bhargava A. (2005). Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum. Proc Natl Acad Sci. 102 (21): 7647-7652.
Comment in: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7409-10.
5. Clifton MS, Hoy JJ, Chang J, Idumalla PS, Fakhruddin H, Grady EF, Dada S, Corvera CU, and Bhargava A. (2007). The Role of Clacitonin Receptor-Like Receptor in Colonic Motility and Inflammation. Am J Physiol Gastrointestinal and Liver Physiology. 293(1): G36-44.
6. Bhargava A*, Jean Philippe V*, Ohara PT*, Kanwar K, Jasmin L. (2008). Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. J. Neuroscience. 28(16): 4161-4171. *: co-first authors.
7. Gavrila AM, Robinson B, Hoy JJ, Stewart J, Bhargava A, Amir S. (2008). Double-stranded RNA-mediated suppression of PER2 expression in the suprachiasmatic nucleus disrupts circadian locomotor activity in rats. Neuroscience. 154(2):409-14.
8. Cureton EL, Ereso AQ, Victorino G, Poole PD, Liao M, Currian B, Harken AH and Bhargava A. Local Secretion of Urocortin 1 Promotes Microvascular Permeability During Lipopolysaccharide-induced Inflammation (2009). Endocrinology. 150(12):5428-37.
Comment in: Comment in: Endocrinology. 2009 Dec; 150(12):5205-7.
9. Jasmin L, Vit JP, Bhargava A, Ohara PT. Can satellite glial cells be therapeutic targets for pain control? Neuron Glia Biol. 2010 Feb;6(1):63-71.
10. Samak G, Suzuki T, Bhargava A, Rao RK. c-Jun NH2-terminal kinase-2 mediates osmotic stress-induced tight junction disruption in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2010 Sep; 299(3):G572-84.
11. Bhargava A*, Pao A*, Di Sole F, Quigley R, Shao X, Wang J, Thomas S, Zhang J, Shi M, Funder JW, Moe O, and Pearce D. Expression and Role of Serum and Glucocorticoid Regulated Kinase 2 in the Regulation of Na+/H+ Exchanger 3 in Mammalian Kidney" by Am J Physio Renal Physiol. 2010 Dec; 299(6):F1496-506.
12. Chang J, Adams MR, Clifton MS, Liao M, Brooks JH, Hasdemir B, and Bhargava A. Urocortin 1 Modulates Immunosignaling in a Rat Model of Colitis via Corticotropin-Releasing Factor Receptor 2. Am J Physiol Gastrointest Liver Physiol. 2011 Feb 17; 300:G884-G894.
13. Bhargava A. CRF and Urocortins: A Challenging Interaction Between Family Members. Gastroenterology. 2011 May; 140(5):1391-4.
14. Liu LS, Qian Li, Sapolsky R, Liao M, Mehta K, Bhargava A, Pasricha PJ. 2011. Transient gastric irritation in the neonatal rats leads to changes in the hypothalamic CRF expression, depression- and anxiety-like behavior as adults. PLoS ONE. 12;6(5):e19498.
15. Hasdemir B, Mahajan S, Bunnett NW, Liao M, Bhargava A. 2012. Endothelin-Converting Enzyme-1 Actions Determine Differential Trafficking and Signaling of Corticotropin-Releasing Factor Receptor 1 at High Agonist Concentrations. Mol Endocrinol. In Press.