Patients with ulcerative colitis (UC) are at increased risk for development of colorectal cancer. Mechanisms of carcinogenesis in this high-risk population, however, remain poorly understood. For this reason, progress in the development of optimal detection and chemoprevention of precancerous lesions has been limited. This proposal will use novel methods combining molecular biology, genomic data, and bioinformatics in order to provide new insights into an area where there is a substantial gap in our knowledge. Success in these studies could greatly advance the current standard of care in inflammatory bowel disease (IBD). The broad objective of this proposal is to test the hypothesis that miR-31, miR-34a, and miR-106b contribute to the development of neoplasia in chronic ulcerative colitis (UC). We further postulate that derangements in pathways involving these miRNAs can be reversed by vitamin D. If successful, this proposal will identify new targets that could improve detection o neoplasia and suggest more effective chemopreventive strategies in IBD. To this end, I propose three specific aims: 1) Determine if mucosal changes in miR-31, miR-34a, and miR-106b precede the development of dysplasia in patients with chronic UC; 2) Identify field effects of key genomic pathways involving miR-31, miR-34a, and miR-106b associated with remote neoplasia in UC; and 3) Investigate the effects of chemopreventive vitamin D on key miRNA-mRNA pathways involving miR-31, miR-34a, and miR- 106b implicated in IBD-cancer. I seek to develop a career as an independent translational gastroenterologist focusing on genomics in inflammatory bowel disease. My long-term research goals are to utilize genomic studies in order to understand mechanisms of carcinogenesis and identify targets for detection and chemoprevention of neoplasia in patients with IBD. My career goals necessitate additional training in genomics and cancer biology. The 5-year career development program outlined in this application will take place at the University of Chicago, which has attained distinction in th clinical care and research of IBD, cancer biology, and genomics and systems biology. Dr. Marc Bissonnette, Associate Professor of Medicine, is my mentor and will provide expertise and guidance in colon cancer biology. Dr. Eugene Chang, Professor of Medicine, is a co-mentor and will provide expertise in molecular aspects of IBD. An inter-disciplinary Advisory Committee comprised of distinguished researchers will provide guidance for me during this development period. This committee is comprised of Dr. Aaron Dinner, an expert in bioinformatics, Dr. John Kwon, an NIH funded physician-scientist with expertise in miRNAs, and Dr. David Rubin, an expert in clinical inflammatory bowel disease research. With the mentorship, education, training, and resources available to me, I will be uniquely equipped to undertake independent translational genomic and systems biology research focused in IBD by the completion of this career development award.

Public Health Relevance

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide, and patients with IBD are at increased risk for the development of cancer. Because there are significant gaps in scientific knowledge as to why cancer develops in this high-risk population, prior efforts to prevent precancerous lesions have been generally unsuccessful. The goal of this proposal is to provide valuable insights into the biology of cancer in IBD, which may improve detection and lead to targeted therapies to prevent the development of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK090152-04
Application #
8850436
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2012-09-01
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Pekow, Joel; Meckel, Katherine; Dougherty, Urszula et al. (2018) Increased mucosal expression of miR-215 precedes the development of neoplasia in patients with long-standing ulcerative colitis. Oncotarget 9:20709-20720
Micic, Dejan; Yarur, Andres; Gonsalves, Alex et al. (2018) Risk Factors for Clostridium difficile Isolation in Inflammatory Bowel Disease: A Prospective Study. Dig Dis Sci 63:1016-1024
Christensen, B; Micic, D; Gibson, P R et al. (2018) Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment Pharmacol Ther 47:753-762
Krugliak Cleveland, Noa; Rubin, David T; Hart, John et al. (2018) Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon. Clin Gastroenterol Hepatol 16:68-74
Micic, Dejan; Gaetano, John N; Rubin, Jonah N et al. (2017) Factors associated with readmission to the hospital within 30 days in patients with inflammatory bowel disease. PLoS One 12:e0182900
Pekow, Joel; Meckel, Katherine; Dougherty, Urszula et al. (2017) miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis-Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD. Clin Cancer Res 23:5281-5291
Yamada, Akihiro; Komaki, Yuga; Patel, Nayan et al. (2017) Risk of Postoperative Complications Among Inflammatory Bowel Disease Patients Treated Preoperatively With Vedolizumab. Am J Gastroenterol 112:1423-1429
Ananthakrishnan, A N; Sakuraba, A; Barnes, E L et al. (2017) The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease. Aliment Pharmacol Ther 46:162-168
Siva, Shivi; Rubin, David T; Gulotta, George et al. (2017) Zinc Deficiency is Associated with Poor Clinical Outcomes in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 23:152-157
Mustafi, Reba; Dougherty, Urszula; Mustafi, Devkumar et al. (2017) ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer. Clin Cancer Res 23:549-561

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