OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Taché, Yvette France eRA COMMONS USER NAME (credential, e.g., agency login): Tache2 POSITION TITLE: Professor of Medicine EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION Univ. of Lyon, Sciences Fac. Lyon, France Univ. of Lyon, Med., Lyon, France Univ. of Montreal Med. Faculty, Montreal, Canada DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Maitrise 07/1969 Maitrise D.E.R.B.E 07/1969 D.E.R.B.E Ph.D. 10/1974 Ph.D. A. Personal Statement In the past decades I have been working in the field of brain-gut interactions and neurogastroenterology. We have pioneered work on the central actions of peptides to influence digestive function, and developed this field through continued competitive grants obtained from the National Institute of Health since 1982, including a NIH Digestive Diseases and Kidney MERIT Award and Veteran Administration Merit Award. I have been mentoring over 60 post doctoral PhD or MD fellows. B. Positions and Honors Positions and Employment 1977 – 1981 Assistant Professor, Dept. of Pediatrics, Faculty of Medicine, Univ. of Montréal, Canada 1978 – 1980 Visiting Scientist, Peptide Biology Laboratory, Salk Institute, La Jolla, CA 1981 – 1982 Associate Professor, Dept. of Pediatrics, Faculty of Medicine, University of Montréal, Canada 1982 – 1985 Associate Professor in Residence, Dept. of Medicine, Faculty of Medicine, UCLA, L.A., CA 1987 – Pres. Professor in Residence, Department of Medicine, Faculty of Medicine, UCLA, Los Angeles, C 1987 – 2000 Associate Director, CURE: Digestive Disease Research Center (DDRC), UCLA Digestive Diseases Division 2000 – 2002 Director CURE NIHDDK- DDRC, UCLA Digestive Diseases, Division 2002 – Pres. Co-Director, Center for Neurobiology of Stress & Women’s Health; Associate Director, CURE/DDRC, UCLA Digestive Division Other Experiences and Professional Memberships 1997-2001 Vice Chair/Chair Hormones and Receptors Council-American Gastroenterology Association 1991 – 1995 Member, NIH Study Section GMA2 1996-present Advisory Board Member, International Foundation for Functional Gastrointestinal Disorders 2000-2004 President, International Society for the Investigation of Stress-President Elect; 2002 President 2004-2008 Council Member, Chair Research Committee, Am. Neurogastroenterology & Motility Society 2005-2009 Council Member, Society of Experimental Biology and Medicine 2005-2011 Steering Committee Member, International Group for Neurogastroenterology and Motility 2006-2011 Executive Committee Member, Gastrointestinal Pharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) Honors 1988 – 1998 Research Scientist Award (National Institute of Mental Health, ADAMHA); 1988 UCLA Woman of Science Award; 1994 Doctor Honoris Causa, Pécs University Medical School, Pécs Hungary; 1996 – 2004 NIH Merit Award; 1998 Janssen Award for Basic Research in Gastroenterology; 2000 – 2015 VA Merit Award; 2003: Distinguished Research Award in Gastrointestinal Physiology (American Physiological Society); 2003 – 2020: Research Career Scientist Award, Dept. of Veteran’s Affairs, Veterans Health Organization; 2005: Senior Investigator Basic Science Award, Intl. Foundation for Functional Gastrointestinal Disorders; 2008: Outstanding AGA Women in Gastroenterology 2008: Research Scientist Award, Functional Brain Gut Research Group 2013: Mentor Award American Gastroenterology Association Council on Neurogastroenterology and Motility 2014: William S. Middleton Award http://www.research.va.gov/about/awards/middleton2014.cfmB. C. Contributions to Science 1. Define the biochemical coding and brain sites regulating gastrointestinal (GI) function under physiological and specific pathological conditions. In the 1980’s as hypothalamic and gut peptides were identified, my independent research provided the foundation for new insight to the role of neuropeptides in the underlying coding of brain-gut interactions. I was the first to establish that bombesin, thyrotropin-releasing hormone (TRH), somatostatin , gastrin releasing peptide corticotropin releasing factor (CRF), calcitonin gene related peptide (CGRP), peptide YY, adrenomedullin urocortin 1, urocortin 2 the cytokine, interleukin-1β (IL1β and more recently, nesfatin-1 act in the brain to influence gastric secretory-motor function in rats or dogs. Using peptides as novel tools to probe brain-gut interactions, we identified specific brain and spinal sites at which these peptides and IL-1β act to influence GI function, namely the paraventricular nucleus of the hypothalamus (PVN,), locus coeruleus complex, dorsal vagal complex (DVC, discrete raphe medullary nuclei, or T9-10 spinal segment and characterized using electrophysiological, surgical and/or pharmacological approaches the autonomic pathways and peripheral transmitters recruited by these brain peptides to exert their influence on gastric acid, and mucus secretion, mucosal blood flow and motor functions. a. Taché Y, Vale W, Rivier J, Brown M. Brain regulation of gastric secretion: influence of neuropeptides. Proc Natl Acad Sci U S A. 1980;77:5515-9. PMID:6159649 b. Martínez V, Rivier J, Coy D, Taché Y. Intracisternal injection of somatostatin receptor 5- preferring agonists induces a vagal cholinergic stimulation of gastric emptying in rats. J Pharmacol Exp Ther. 2000;293:1099-105. PMID:10869415 c. Kosoyan HP, Grigoriadis DE, Taché Y. The CRF(1) receptor antagonist, NBI-35965, abolished the activation of locus coeruleus neurons induced by colorectal distension and intracisternal CRF in rats. Brain Res. 2005;1056:85-96. PMID:16095571 d. Czimmer J, Million M, Taché Y. Urocortin 2 acts centrally to delay gastric emptying through sympathetic pathways while CRF and urocortin 1 inhibitory actions are vagal dependent in rats. Am J Physiol Gastrointest Liver Physiol. 2006;290:G511-8 2. Discovery that the three amino-acid peptide, TRH located in the brain medulla is the main physiological stimulant of vagal outflow to the stomach independently from its pituitary action. In particular we were the first to show that a) TRH injected into the cisterna magna or selectively into the DVC, induces a vagal-dependent activation of gastric cholinergic myenteric neurons and motility, stimulation of the gastric mucosal release of acid, histamine, serotonin, gastrin, ghrelin, mucus, and increased gastric mucosal blood flow; b) the activation of raphe pallidus, raphe obscurus, or parapyramidal nuclei containing TRH synthesizing neurons innervating the DVC, induces a vagal-dependent stimulation of gastric secretory-motor function and elevation of circulating insulin which is mediated by endogenous TRH action onto DVC neurons; c) brain medullary TRH mediates the vagal dependent stimulation of gastric acid induced by sham feeding, and emptying induced by acute cold exposure; d) Using activation of TRH signaling pathways in the brain medulla as a physiological probe to activate the vagus at different intensities, we unraveled the dual gastroprotective or erosive impact of the vagus and peripheral mediators involved. A low level of TRH receptor activation, elicited by exogenous or endogenous TRH in the DVC, induces a vagal dependent gastric protection against experimental erosions brought about by the vagal dependent increase in gastric mucus secretion, prostaglandin (PG)E2,- nitric oxide- and CGRP-dependent mechanisms including increased mucosal blood flow while acid secretion is inhibited by the dual actions of PGE2 and CGRP. By contrast, maximal TRH receptor activation in the DVC induces a vagal cholinergic dependent increased in histamine, gastrin and related acid hypersecretion, along with sustained gastric motility response contributing to gastric erosions. This brain medullary TRH pathway underlies cold exposure induced gastric erosions. These findings are described in 92 publications in Pub Med. a. Taché Y, Vale W, Brown M. Thyrotropin-releasing hormone--CNS action to stimulate gastric acid secretion. Nature. 1980;287:149-51. PMID 6776408 b. Yoneda M, Taché Y.Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats. Gastroenterology. 1992 ;102:1568-74. PMID:1568566 c. Martinez V, Wu SV, Taché Y. Intracisternal antisense oligodeoxynucleotides to the thyrotropinreleasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats. Endocrinology. 1998;139:3730-5. PMID: 9724024 d. Taché Y, Yang H, Miampamba M, Martinez V, Yuan PQ. Role of brainstem TRH/TRH-R1 receptors in the vagal gastric cholinergic response to various stimuli including sham-feeding. Auton Neurosci. 2006;125:4252. PMID: 16520096 3. Establish the role of brain and gut CRF receptor signaling in stress-related alterations of gut motility and visceral hypersensitivity. This was shown by demonstrating that a) CRF and related peptides, urocortins act at specific brain sites that alter autonomic outflow leading to inhibition of gastric transit and motility; b) brain CRF signaling pathways is involved in the delayed gastric emptying induced by psychological (restraint), immune (increased cytokines into the circulation or the brain), and visceral (surgery) stressors; c) In the lower gut, the activation of CRF receptors in the PVN and coeruleus /subcoeruleus is involved in the stimulation of colonic motor function through activation of sacral parasympathetic outflow; d) this pathways has relevance in the defecation, diarrhea and visceral hypersensitivity responses induced various acute or repeated psychological stressors. e) In addition to the brain, the gut is endowed with a CRFsignaling system that exerts a role as a local effector of the central autonomic pathways involved in the GI response to stress. CRF/urocortins and CRF receptor subtypes including new isoforms were identified in layers of upper gut and colon in rats and human tissues. Peripheral activation of CRF1 receptor was shown to recapitulate key features of symptoms in diarrhea-predominant IBS, such as the stimulation of colonic myenteric neurons, motility, defecation/watery diarrhea, visceral hypersensitivity to colorectal distention, increased intestinal permeability in rodents. a. Taché Y, Goto Y, Gunion MW, Vale W, River J, Brown M. Inhibition of gastric acid secretion in rats by intracerebral injection of corticotropin-releasing factor. Science. 1983;222:935-7. PMID:6415815 b. Mönnikes H, Schmidt BG, Taché Y. Psychological stress-induced accelerated colonic transit in rats involves hypothalamic CRF. Gastroenterology. 1993;104:716-23. PMID:8440432 c. Taché Y, Bonaz B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest. 2007117:33-40. Review. PMID: 17200704 d. Larauche M, Gourcerol G, Wang L, Pambukchian K, Brunnhuber S, Adelson DW, Rivier J, Million M, Taché Y. Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. Am J Physiol Gastrointest Liver Physiol. 2009;297:G215-27. PMID: 18308857 4. Gut-Brain Peptides Signaling and the Regulation of Food and water Intake. An important aspect of gut peptides is the regulation of their co-release depending upon the metabolic status. We identified a synergistic interaction between leptin and cholecystokinin (CCK) to induce satiety in rodents exerted a the levels of capsaicin sensitive vagal afferents. CCK and urocortin 1 also act synergistically to suppress food intake through CRF2 receptors on gastric vagal afferents, a response that is lost in high-fat diet-induced obesity Other recent work related to nesfatin-1 and dypsogenic action of brain somatostatin. a. Barrachina MD, Martínez V, Wang L, Wei JY, Taché Y Synergistic interaction between leptin and cck to reduce short-term food intake in lean mice. Proc Natl Acad Sci U S A. 1997 ;94:10455-60. PMID 9294232 b. Gourcerol G, Wang L, Wang YH, Million M, Taché Y. Urocortins and cholecystokinin-8 act synergistically to increase satiation in lean but not obese mice: involvement of corticotropin-releasing factor receptor-2 pathway. Endocrinology. 2007;148:6115-23. PMID 17932219 c. Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Mönnikes H, Lambrecht NW, Taché Y.Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropinreleasing factor2 receptor. Endocrinology. 2009;150:4911-9. PMID: 19797401 d. Karasawa H, Yakabi S, Wang L, Stengel A, Rivier J, Taché Y. Brain somatostatin receptor 2 mediates the dipsogenic effect of central somatostatin and cortistatin in rats: role in drinking behavior. Am J Physiol Regul Integr Comp Physiol. 2014 ;307:R793-801 PMID: 25031229 Complete List of Published Work in MyBibliography: http://www.ncbi.nlm.nih.gov/pubmed/?term=Tache+y D. Research Support ONGOING VA Middleton Award (Y. Taché, PI) 10/01/14 – 09/30/17 Department of Veteran Affairs Peripheral Mechanisms of Post-Operative Ileus The objective is to assess the mechanisms underlying post-operative ileus with emphasis on stress related alterations of autonomic nervous and enteric nervous systems. NIH 2 P50 DK064539-11 (E. Mayer, PI) 09/30/12 – 08/31/17 Project 1 (Y. Taché, co-PI) and 2C (co-investigator) Women’s Health and Functional Visceral Disorder Center The goal of project 1B is to establish that perinatal stress alters the pattern of regional brain CRF and CRFR1 expression, and DNA methylation of glucocorticoid receptor promoter region in male and female rats. 2C: To establish a CRF-related sex difference in visceral adipose adipokine expression and differential brain regional alterations in a mouse model of constitutive HPA hyperactivity. NIH 2 P30 DK041301-26 (E. Rozengurt, PI) 11/30/09– 1/12/19 Digestive Diseases Center Animal Core (Y.Taché, PI) The animal core provides guidance and expertise in the performance of in vivo studies and to assess gut motor functions, visceral pain, and experimental models of stress and food intake monitoring to test in vivo biological activity of new peptides agonists/antagonists. (Y. Taché, PI) 09/01/13 – 05/31/16 NIH 2R01-57238-11A1 Peripheral Mechanisms of Stress-induced Activation of Colonic Motor Function. This is grant to characterize stress-induced visceral analgesia (SIVA) in adult naïve and maternally separated rats (aim 1), to unravel the neurochemistry of SIVA: role brain CRF and oxytocin (aim 2) and to delineate the novel CRF-POMC-β-endorphin system expressed in the colon and its role as a local modulator of visceral pain. Department of Veteran Affairs Merit Award (J. Pisegna, PI, Y. Taché, co-PI) 01/10/10-10/31/15 Department of Veteran Affairs F7219R Gastrointestinal Hormonal Regulation of Obesity The objective of the proposal is to investigate the influence of high protein diet in obese subjects and wester-diet induced obese rats on body weight lost, food intake and gut hormone release. . COMPLETED NIDDK R01 DK 33061 Corticotropin-Releasing Factor: Biological Action on Gastric Function Principal Investigator