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1 NAME: Lin Chang, M.D. OMB No /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. era COMMONS USER NAME (credential, e.g., agency login): changl2 POSITION TITLE: Professor of Medicine in Residence 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 DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY University of California, Los Angeles, CA B.S Biochemistry UCLA School of Medicine M.D Medicine Harbor-UCLA Medical Center M.D Internal Medicine UCLA Affiliated GI Fellowship Training Program M.D Gastroenterology A. Personal Statement. I serve as Co-Director of the Oppenheimer Family Center for Neurobiology of Stress, an interdisciplinary center with a research and clinical focus on the interactions of pain, stress and emotions in health and disease. I am also Co-Director of the Administrative Core of our Center s NIH Specialized Centers of Research (SCOR), which studies sex differences in chronic visceral pain disorders, including irritable bowel syndrome (IBS) and am PI of Project 1 of the SCOR. I serve as a Co-Leader of the UCLA CTSI Clinical and Community Research Resource Program, Operations Committee and Scientific Review Committee. I am also Program Director of the UCLA GI Fellowship Program. My research has focused on pathophysiologic mechanisms, clinical symptoms, health outcomes, and treatment in IBS. I have extensive experience in the area of stress-induced hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses, pain sensitivity, sex-related differences, gene expression profiling from colonic tissue and peripheral blood mononuclear cells and health outcomes in IBS. I have mentored 3 gastroenterology fellows on the UCLA Gastroenterology T32 training grant in addition to clinical GI fellows, medical students, medical residents, post-docs, and visiting scientists.with regard to other professional activities, I recently served as President of the American Neurogastroenterology and Motility Society (ANMS), and am also a member of the Rome Foundation Board of Directors and the Rome IV Editorial Board and the Functional Bowel Disorders Committee. I am a fellow of the American Gastroenterological Association and American College of Gastroenterology, and a member of the Society for Neuroscience. For the past 6 years, I have been an Associate Editor of the American Journal of Gastroenterology. I also served on the FDA GI Advisory Panel. I have given many invited lectures and presentations at national and international meetings. B. Positions and Honors. Positions and Employment Associate Consultant, Gastroenterology, Mayo Clinic, Rochester, MN Assistant Professor of Medicine, UCLA School of Medicine, Department of Medicine, Div. of Gastroenterology, Harbor-UCLA Medical Center Assistant Professor of Medicine, UCLA School of Medicine, Div. of Digestive Diseases, UCLA Associate Professor of Medicine, UCLA School of Medicine, Div. of Digestive Diseases, UCLA. Co-Director, Center for Neurovisceral Sciences and Women s Health at UCLA Associate Director, UCLA GCRC 2006 Present Professor of Medicine in Residence, UCLA School of Medicine, Div. of Digestive Diseases, UCLA. Co-Director, Oppenheimer Family Center for Neurobiology of Stress 2011 Present Co-Leader, Clinical & Translational Science Institute (CTSI) - Clinical & Community Research Resource (CCRR) Program

2 2012 Present Director, UCLA Digestive Health and Nutrition Clinic 2013 Present Program Director, UCLA GI Fellowship Program Honors 1995 Auxiliary Award, American College of Gastroenterology 2002 Janssen Award in Gastroenterology, Basic or Clinical Research 2002 Women in Gastroenterology and Wyeth Award for Gender Based Research, ACG 2009 AGA Distinguished Clinician Award C. Contribution to Science 1. The role of sex differences in the clinical presentation and pathophysiology of IBS. Our research center has been funded with a SCOR (Specialized Center of Research) grant by the NIH Office of Research in Women s Health and by NIDDK since Currently the only NIH-funded center in the area of brain-visceral interactions, it is an interdisciplinary research and clinical center, which studies bi-directional mechanisms by which the central nervous system and the viscera interact in health and disease, with an emphasis on sex differences. I have served as PI of one of the projects within the SCOR. My research has focused on the observation that IBS is a female predominant, stress-sensitive disorder that is associated with stress-induced exacerbations of abdominal pain and other GI symptoms. Our studies demonstrated sex and gender differences in clinical symptoms, visceral perception, autonomic nervous system function, central brain activation patterns, peripheral immune markers, and stress response to a visceral stressor. Specifically, we found that: 1) Women are more likely to report abdominal pain, constipation and bloating with visible abdominal distension than men; 2) Sex significantly influences perceptual sensitivity to rectosigmoid distension with IBS women showing greater perceptual responses, which could explain the greater vulnerability to visceral pain in women; 3) Sex differences in the central response to a visceral stimulus exist with women showing greater activation in brain regions concerned with emotional arousal and men showing greater activation in regions concerned with cognitive responses to pain; 4) Men with IBS have a greater cardiosympathetic/vagal balance in response to colonic stimulation compared to women with IBS; 5) Women with IBS were found to have decreased colonic mucosal expression of the anti-inflammatory cytokine, IL-10, and NK-1 receptors compared to healthy women and men with IBS suggesting that colonic mucosal inflammation does not have a consistently primary role in these patients but that the finding of decreased IL-10 mrna expression suggests an altered colonic immune response may exist in women with IBS; and 6) Men with IBS have an enhanced stress hormone response (i.e., cortisol levels) to hormone stimulation and a visceral stressor in IBS but this finding was mainly found in men and not women. Taken together, our research demonstrates that sex and gender effects in brain-gut interactions involved in pain perception and stress response exist in IBS and help to explain the female predominance in IBS and sex differences in clinical symptoms. 1. Chang L, Mayer EA, Labus J, Schmulson M, Lee OY, Olivas TI, Stains J, Naliboff BD. Effect of sex on perception of rectosigmoid stimuli in irritable bowel syndrome. Am J Physiol-Regulatory, Integrative and Comparative Physiology 291:R277-R284, Adeyemo M, Spiegel BMR, Chang L. Do Irritable Bowel Syndrome (IBS) Symptoms Vary Between Men and Women? A Meta-Analysis and Systematic Review. Alimentary Pharmacology and Therapeutics 2010;32: PMCID: PMC Chang L, Adeyemo M, Karagiannides I, Videlock EJ, Bowe C, Shih W, Presson AA, Yuan PQ, Gong H, Singh S, Cortina G, Licudine A, Tache Y, Pothoulakis C, Mayer EA. Serum and colonic immune markers in irritable bowel syndrome. American Journal of Gastroenterology 2012;107(2): PMCID: PMC Naliboff BD, Berman S, Chang L, Derbyshire SWG, Suyenobu B, Vogt BA, Mandelkern MA, Mayer EA. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 124: , The role of chronic stress and early adverse life events in IBS. One of my longstanding research interests is the role of stress in IBS. We and others have demonstrated evidence that IBS is a stress-sensitive disorder. Current stress is associated with the onset and symptom flares in IBS. Past studies found that chronic stress in the form of sexual, emotional and physical abuse is more prevalent in IBS patients compared to healthy individuals. In addition to a higher prevalence of abuse in IBS patients, we demonstrated that these patients have higher prevalence of general traumatic events during

3 childhood, including a history of mental illness in a household member and that stressful life events are associated with overall greater IBS symptom and pain severity. My research has focused on studying the central stress response in IBS, specifically the hypothalamic-pituitary-adrenal (HPA) axis. Overall, alterations in HPA axis function have been shown in IBS, although most studies evaluated the stress response to an experimental stressor, e.g. mental stress. We measured basal tone and circadian rhythm of the HPA axis over a 24-hour period in patients with IBS and found that it was dysregulated compared to healthy controls. We also studied stimulated HPA axis hormone responses, specifically to a visceral stressor and to a pharmacologic stimulation (hormone challenge). In response to a visceral stressor (i.e., sigmoidoscopy), both IBS patients and healthy individuals had an increased cortisol response if they had a history of early adverse life stressors. In IBS patients, a slower recovery from peak levels was associated with increased severity of IBS symptoms. In response to pharmacologic stress hormone challenges (i.e., corticotropin releasing hormone [CRH] and adrenocorticotropin hormone [ACTH]), IBS patients had a slower decline and recovery from peak levels of ACTH and cortisol. There was also a significant disease (IBS vs. healthy control) and sex interaction where men with IBS had higher cortisol responses compared to healthy men, while women with IBS had lower responses to healthy women. Similar to depression and post-traumatic stress disorder (PTSD), we have found that the HPA axis function is altered and correlates with glucocorticoid receptor expression in peripheral blood mononuclear cells (PBMC) suggesting that the latter can be a reflection of HPA axis sensitivity to negative feedback. Taken together, our findings support that alterations in HPA axis function exist in IBS and may be due at least in part to experiencing chronic stress in early life and adulthood and decreased negative feedback via glucocorticoid receptors. 1. Chang L, Sundaresh S, Elliott J, Anton PA, Baldi P, Licudine A, Mayer M, Vuong T, Hirano M, Naliboff BD, Ameen VZ, Mayer EA. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome. Neurogastroenterology and Motility 2009;21: PMCID: PMC Videlock E, Adeyemo M, Licudine A, Hirano M, Ohning G, Mayer M, Mayer EA, Chang L. Childhood trauma is associated with increased hypothalamic-pituitary-adrenal (HPA) axis responsiveness in irritable bowel syndrome. Gastroenterology 2009;137: PMCID: PMC Chang L. The role of stress on physiologic responses and clinical symptoms in IBS. Gastroenterology 2011;140(3): PMCID: PMC Bradford K, Shih W, Videlock E, Presson AP, Naliboff BD, Mayer EA, Chang L. Association of early adverse life events and irritable bowel syndrome. Clinical Gastroenterology and Hepatology 2012;10(4): PMCID: PMC Mechanisms underlying somatic and visceral pain perception in health and the chronic pain syndromes IBS and fibromyalgia Human studies have demonstrated that IBS often coexists with other chronic pain syndrome, most notably fibromyalgia. My research focused on testing a neurobiological model relevant to patients with IBS and fibromyalgia to explain the wide range of symptoms within each patient population, and the overlap of symptoms between the two groups. Specifically, we wanted to address whether altered pathophysiologic mechanisms associated with chronic pain were shared by these two disorders. I received the NIH grants, Clinical Associate Physician (CAP) Award and a R01, by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for this research. This model postulated that stress-induced alterations in central nervous system circuits, referred to as the emotional motor system, resulting in an inadequate antinociceptive response, altered autonomic (e.g., sympathetic nervous system) and HPA axis responses, and cognitive amplification of pain via hypervigilance and hyperattentiveness towards viscerosomatic stimuli. We found that: 1) IBS and fibromyalgia are stress-related conditions with evidence of a dysregulated basal circadian rhythm of the HPA axis; 2) Both IBS and fibromyalgia are characterized by hyperalgesia, specifically visceral hyperalgesia in IBS and somatic hyperalgesia and both in patients with overlapping IBS and fibromyalgia; and 3) Increased activation of the anterior cingulate cortex subregion involved in attentional and sensory mechanisms occurs in IBS patients in response to visceral pain stimulation and in fibromyalgia patients in response to somatic pain stimulation. In addition, a better understanding of the cortical processes underlying visceral and somatic pain in healthy subjects was demonstrated in our brain imaging studies. We found differences in the cortical processing of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness and during attentional modulation. Furthermore, differences in the activation of the periaqueductal gray and nucleus cuneiformis, which are involved in the nociceptive response, represented a greater nocifensive response and emotive salience of visceral over somatic pain.

4 1. Chang, L, Berman S, Mayer EA, Suyenobu B, Derbyshire SWG, Naliboff BD Vogt B, FitzGerald LZ, Mandelkern MA. Brain responses to acute visceral and somatic stimuli in patients with irritable bowel syndrome and fibromyalgia. Am J Gastroenterol 2003;98: Chang L, Sundaresh S, Elliott J, Anton PA, Baldi P, Licudine A, Mayer M, Vuong T, Hirano M, Naliboff BD, Ameen VZ, Mayer EA. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome. Neurogastroenterology and Motility 2009;21: PMCID: PMC Dunckley P, Wise RG, Fairhurst M, Hobden P, Aziz Q, Chang L, Tracey I. A comparison of visceral and somatic pain processing in the human brainstem using fmri. J Neurosci 25(32): , Dunckley P, Aziz Q, Wise RG, Brooks J, Tracey I, Chang L. Attentional modulation of visceral and somatic pain. Neurogastroenterology and Motility; 19(7):569-77, Health outcomes in IBS. I have conducted clinical research studies including health services research and clinic treatment trials in IBS for 20 years and this work has resulted in 35 peer-reviewed papers. Our Center has compiled a large and comprehensive database of clinical and physiologic data collected in IBS patients, healthy individuals and other patient groups with chronic visceral or somatic pain. This database has resulted in key findings in IBS including: 1) Characterization of GI and extraintestinal symptoms in IBS and bowel habit subtypes; 2) Predictors of symptom severity and health-related quality of life; and 3) sex and gender differences in clinical presentation. I also served as Co-PI in the development of a multicenter cohort of IBS patients (IBS Proof Cohort) in the U.S. where a series of studies measured patient reported outcomes and valid and reliable health utilities, and developed a framework for IBS symptoms for use in clinical trials. For the past 4 years, I served as a co-investigator on a U01 NIH Patient Reported Outcomes Measurement Instrument System (PROMIS) grant to develop the first GI symptom scale that was validated to measure GI symptom severity in patients with a variety of GI diseases as well as in the general population. There are 8 GI symptom domains including heartburn, dysphagia, nausea and/or vomiting, abdominal pain, diarrhea, constipation, fecal incontinence, gas and bloating. Three years ago, we obtained a large, investigator-initiated grant to develop an automated internet-based GI symptom assessment using the GI PROMIS symptom scale and educational platform, including educational videos, to be used by patients and clinicians in GI practices. I have served on the FDA GI Advisory Panel including being the Chair and was the Course Director of the Rome Foundation Endpoints and Outcomes Conference whose participants including the FDA, scientists, clinicians and industry. 1. Spiegel BMR, Strickland A, Naliboff BD, Mayer EA, Chang L. Predictors of patient-assessed illness severity in irritable bowel syndrome. American Journal of Gastroenterology 2008;103(10): PMCID: PMC Spiegel BMR, Bolus RE, Harris LA, Lucak SL, Mayer EA, Naliboff BD, Chey WD, Sayuk G, Esrailian E, Lembo A, Karsan HA, Tillisch K, Talley J, Chang L. Characterizing abdominal pain in IBS: guidance for study inclusion criteria and outcome measurement. Alimentary Pharmacology and Therapeutics 2010;32(9): PMC Naliboff BD, Kim S, Bolus R, Bernstein CN, Mayer EA, Chang L. Gastrointestinal and Psychological Mediators of Health Related Quality of Life in IBS and IBD: A Structural Equation Modeling Analysis. American Journal of Gastroenterology 2012;107: PMCID: PMC Spiegel BM, Hays R, Bolus R, Melmed G, Chang L, Whitman C, Khanna PP, Paz SH, Hays T, Reise S, Khanna D. Development of the NIH Patient Reported Outcomes Measurement Information System (PROMIS ) Gastrointestinal Symptom Scales. American J Gastroenterology 2014;109(11): PMC Full list of published work: ding D. Research Support Ongoing Research Support 1P50 DK64539 (PI:Mayer) 09/01/12 08/31/17 NIH P50 Center Grant Center for Neurovisceral Sciences and Women s Health Project 1: HPA Axis Dysregulation in IBS and Related Animal Models, with Emphasis on Sex Differences (Chang)

5 The goals are to focus on the identification of a biological marker for IBS and associated alterations in the stress response systems, and on a translational approach in rodents to identify alterations in CRF-R1 signaling and GR promoter methylation in specific brain regions and circuitries following early life stress. There is no overlap with the current grant proposal. Role: Co-PI of SCOR, PI of Project 1 1UL1 RR (PI: Dubinett) 06/01/11-02/29/16 NIH/NCRR Clinical & Translational Science Institute (CTSI) The goals of this project are to eliminate barriers and enhance collaboration and growth among the basic, biomedical, clinical, and population-based sciences so as to accelerate the pace and increase the volume of scientific discoveries and their translations to innovative tools and practices in human disease diagnosis, treatment, and prevention. Role: Co-Leader, Clinical & Community Research Resource (CCRR) Program Rome Foundation (PI: Chang) 04/01/15-10/31/15 Multicenter Validation Study on the Rome IV Diagnostic Criteria for Functional Gastrointestinal Disorders The goals of this multicenter study is to assess the degree of agreement of Rome IV diagnoses of FGIDs with clinical diagnoses made by expert gastroenterologists in multiple settings, to test how well Rome IV diagnoses agree with Rome III diagnoses for IBS, functional dyspepsia, and constipation, and to evaluate the two-week test-retest reliability of common Rome IV diagnoses. Role: Site PI Completed Research Support 1P50 DK64539 (PI: Mayer) 09/01/07 08/31/12 NIH P50 Center Grant Center for Neurovisceral Sciences and Women s Health Project 2: Sex differences in mucosal neuron-endocrine-immune interactions in IBS patients and relationship to symptoms (Chang PI) The goals of this project are: 1) To identify sex differences in the expression of the colonic mucosal CRF signaling system. 2) To explore the relationship of the CRF signaling system and T lymphocytes in the colonic mucosa and lamina propria by examining whether lamina propria T lymphocytes from IBS patients have altered CRF receptor (CRFR) expression, and if it is consistent between men and women and IBS vs. controls. 3) To explore the possible relationships between mucosal CRF signaling alterations and central measures of increased stress responsiveness, and if these relationships are consistent between men and women and IBS vs. controls. NIH/NIAMS R01 AR (PI: Chang) 07/01/99 01/31/12 Neuroendocrine Alterations in Fibromyalgia and IBS This study assesses the neuroendocrine alterations, brain activation patterns in response to somatic and visceral pain, and the role of enhanced pain amplification mechanisms of heightened attention and symptomspecific anxiety in IBS and fibromyalgia. Role: PI P30 DK (PI: Rozengurt) 12/01/04 11/30/14 NIH/NIDDK CURE: Digestive Diseases Research Core Center The CURE: Digestive Diseases Research Core Center is composed of a cohesive group of physicians and basic scientists with strong independent peer-reviewed grant-supported research programs in the biology of the gut, with special emphasis upon regulation of mucosal cell function, gut neuroscience and signal transduction mechanisms. Role: Co-Director, Human Studies Core 1 U01 AR (Co-PI: Khanna/Spiegel) 10/01/09-07/31/13 NIH/NIAMS

6 Development and Initial Validation of PROMIS GI Distress Scale. The goals of this project are to develop a GI Distress item pool and evaluate its psychometric properties in three patient groups: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and scleroderma. Role: Co-I Investigator-initiated (Chang) 02/01/12 07/31/14 Ironwood A Pilot Study Evaluating Guanylate Cyclase C Receptor and Ligand Expression in Colonic Mucosa in Irritable Bowel Syndrome with Constipation and Chronic Constipation The goals are to: 1) To compare guanylate cyclase C (GC-C) receptor, guanylin and uroguanylin mrna expression colonic mucosa of individuals with IBS-C, chronic (functional) constipation (CC), and healthy controls, and 2) To compare protein levels of guanylin, uroguanylin, and GC-C receptors in the colonic mucosa of individuals with IBS-C, chronic constipation (CC), and healthy controls. Ironwood Investigator-initiated (PI: Spiegel, Chey) 10/1/11-10/31/14 Development and Validation of The Automated Evaluation of GastroIntestinal Symptoms (AEGIS) Platform The goals of this project are to develop and validate an automated system administered through electronic portals to collect, categorize, and interpret gastrointestinal (GI) symptoms in a uniform and clinically useful manner and to provide clinically relevant educational materials for patients. AEGIS will be designed for use within everyday practice to help clinicians perform assessments and provide tailored feedback to their GI patients. Role: Co-I