Since its initial funding through a SCOR grant in 2002, the UCLA Center for Neurovisceral Sciences and Women's Health has pursued the general hypothesis that many functional disorders, including irritable bowel syndrome (IBS) and interstitial cystitis/painful bladder syndrome (IC/PBS), are related to enhanced stress responsiveness, and that the greater prevalence of these syndromes in women is related to sex related differences in responses to perturbations of homeostasis. Building on results generated during the past 2 funding periods, the current proposal aims to apply novel conceptual, technical and analytical tools to address the following interdisciplinary theme, "Sex-Related Individual Differences in Central Stress Response Systems and Their Role in IBS Pathophysiology and Treatment Response." We propose to test the general hypothesis that subsets of patients can be identified which are characterized by unique clusters of central and peripheral endophenotypes, and which may show differential responsiveness to treatment. The 3 Projects of the SCOR, supported by two scientific Cores will address two overarching themes: 1) Hypothalamic-Pituitary-Adrenal (HPA) axis and central stress systems, and 2) Endophenotype-based subgrouping of IBS patients. We will address these 2 themes through 3 synergistic, translational research Projects, with an emphasis on sex differences. Project 1 will conduct a comprehensive genetic, molecular and functional phenotyping of the HPA axis in IBS patients and healthy controls establish regional brain CRF/CRF1R expression and delineate engagement of central stress circuits in an animal model of IBS. Project 2 will test the hypothesis that chronic stress in IBS is associated with HPA axis dysregulation, increased visceral adipose tissue (VAT) accumulation and circulating adipokines, which modulate HPA axis responsiveness, and mediate regional brain changes. Project 3 will perform comprehensive endophenotyping using biomarkers collected from all 3 Projects within a large group of IBS patients to identify unique clusters of endophenotypes, and distinguish a subgroup with an upregulated CRF/CRF1R signaling system who can be identified by their responsiveness to a selective CRFIR antagonist.

Public Health Relevance

IBS and IC/PBS are common, female predominant visceral pain conditions, but reasons for this gender bias are poorly understood. These stress-sensitive disorders are highly prevalent, can be associated with a poor quality of life and burdened by the lack of consistently effective treatments. The proposal aims to identify the biologic mechanisms that are responsible for increased stress sensitivity in IBS, determine if these biomarkers can identify a subset of patients and predict response to treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK064539-13
Application #
8733656
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (50))
Program Officer
Hamilton, Frank A
Project Start
2002-09-30
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
$957,147
Indirect Cost
$307,147
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hoffman, Jill M; Baritaki, Stavroula; Ruiz, Jonathan J et al. (2016) Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. Am J Pathol 186:134-44
Gupta, Arpana; Labus, Jennifer; Kilpatrick, Lisa A et al. (2016) Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females. Brain Struct Funct 221:1667-79
Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy et al. (2016) Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats. PLoS One 11:e0155037
Hong, J-Y; Naliboff, B; Labus, J S et al. (2016) Altered brain responses in subjects with irritable bowel syndrome during cued and uncued pain expectation. Neurogastroenterol Motil 28:127-38
Padua, David; Pothoulakis, Charalabos (2016) Novel approaches to treating Clostridium difficile-associated colitis. Expert Rev Gastroenterol Hepatol 10:193-204
Videlock, Elizabeth J; Shih, Wendy; Adeyemo, Mopelola et al. (2016) The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression. Psychoneuroendocrinology 69:67-76
Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W et al. (2016) Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 6:22195
Park, S H; Videlock, E J; Shih, W et al. (2016) Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. Neurogastroenterol Motil 28:1252-60
Duboc, H; Tolstanova, G; Yuan, P-Q et al. (2016) Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil 28:1663-1676
Million, M; Larauche, M (2016) Stress, sex, and the enteric nervous system. Neurogastroenterol Motil 28:1283-9

Showing the most recent 10 out of 190 publications