Research in IBD at University of Colorado Denver

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1 Research in IBD at University of Colorado Denver Blair Fennimore, MD Assistant Professor of Medicine Division of Gastroenterology and Hepatology UCH Crohn s and Colitis Center Mucosal Inflammation Program

2 Epidemiology of PSC-IBD ~1.4 million with IBD in the US ~5% of UC with PSC Up to 90% of PSC with UC >50,000 with IBD in the Mountain West >12,000 along the front range Gastro 2004:126; NEJM 1995:332;

3 Major Regional IBD Centers Rochester, MN Chicago Denver Los Angeles

4 IBD Research Model at UCH Three highly collaborative clinical and basic science research arms Crohn s and Colitis Center Children s Hospital Colorado Pediatric Inflammatory Bowel Disease Center

5 4 P s Physical Proximity Promotes Partnership Mucosal Inflammation Program University of Colorado Hospital Crohn s & Colitis Center Children s Hospital Colorado Pediatric Inflammatory Bowel Disease Center Anschutz Medical Campus Aurora, Colorado

6 A multi-disciplinary center of excellence committed to the identification of novel targets for diagnosis and directed therapy of mucosal disease.

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8 Cumulative Funding, million Cumulative Funding ($Direct + F&A), million Mucosal Inflammation Program 2007 n= n=49 5 labs 7 specialties Private Donations Foundations 10% 7% 10% Other 7% Fiscal Year NIH 80% 80%

9 Inflammatory Bowel Disease Pathogenesis ~150 genes Complex heredity Genetics Immune System Cytokine Imbalance Immune Medications IBD Environment Gut Bacteria

10 Immunity of IBD Meta-analysis of GWAS (CD 2010, UC 2011) ~150 SNP s 99 total disease loci 28 shared loci >85% of IBD genes relate to Innate Immunity Nature 2011:474;307

11 Ongoing Work in Innate Immunity Autophagy Neutrophil Trafficking Angiogenesis Shifts in the Microbiome Nucleotide Metabolism Oxygen Metabolism

12 Hypoxia in IBD Hypoxia = Low Oxygen Normal Colitis

13 Hypoxia Inducible Factor - HIF α β + = α β HIF Normoxia Hypoxia O 2 O 2 α O 2 α HO α α Hypoxia α HO α α + β α β Gene Transcription DNA

14 HIF in Mouse Models of Colitis HIF Knockout Mice DSS Colitis Body weight Barrier Healthy Mice Control Colitis Mutant Colitis + - Colitis

15 HIF in Mouse Models of Colitis AKB-4924 Treatment HIF Stabilizer ( HIF levels) O 2 O 2 O 2 α α β α Body weight Healthy Mice Disease Activity Colitis Colitis + AKB-4294 Colitis + Steroids Colitis Colitis + Steroids Colitis + AKB-4294 Healthy Mice

16 HIF in Mouse Models of Colitis Colitis Healthy Colitis + AKB-4294 HIF is protective in colitis AKB-4924 (HIF mimetic) is a potential therapeutic option Phase I Clinical Trials

17 Creatine Metabolism P ATP ADP Creatine Creatine Kinase P Phospho Creatine P ATP

18 Creatine as a Biomarker in Colitis Creatine Concentration TNBS Colitis Healthy Colitis Creatine Phospho Creatine PCr/Cr Ratio

19 Decreased Levels of CK in Human IBD Creatine Kinase Levels in IBD CK Staining in IBD Normal Normal Crohn s UC Abnormal Creatine/Phospho- Creatine Pathway in IBD Ulcerative Colitis PNAS 2013:110;

20 Creatine Supplements in Colitis Healthy Colitis Colitis + 2% Cr Creatine supplementation improved colitis severity in a mouse model

21 UCH Crohn s and Colitis Center Crohn s and Colitis Center

22 UCH Crohn s and Colitis Center

23 Clinical Research in IBD at UCH RESEARCH IBD Database Umbrella protocol Disease Phenotype Disease Activity Measures Biorepository: > 500 patients Serum Tissue Clinical Trials: CCFA Clinical Research Alliance - MERIT-UC - PUCCINI Industry-Sponsored studies - Placental Stem Cell infusions Investigator-Initiated studies - Creatine supplementation IBD Clinic POPULATION MGMT Evidence-Based Care QI Initiatives Performance Measurement - PQRS: AGA BTE Program

24 Clinical Research Trials MERIT-UC NIH funded study using Methotrexate in UC PUCCINI Study to clarify the risks associated with the use of IBD medications at the time of surgery Placental Stem Cell Infusion Study of placental stem cell infusions as adjunct therapy in severe/refractory Crohn s disease Creatine Supplementation in UC Study of Creatine supplementation in treatment of mild-moderate UC

25 IBD Research at UCH Exciting ongoing research through the MIP and UCH Crohn s and Colitis Center Basic science Translational research Clinical trials in new IBD therapies Quality improvement initiatives in patient care Multidisciplinary approach to clinical IBD care

26 Thank You