The pathogenesis of Crohn's disease involves chronic intestinal inflammation that waxes and wanes over time. After years of inflammation, patients develop intestinal fibrosis that can lead to strictures, fistulae and obstruction. Existing medications treat inflammation, but no available medications prevent fibrosis or treat established fibrosis. One of the major stumbling blocks to developing and studying effective drugs is the lack of a non-invasive test for fibrosis. Small bowel radiography can demonstrate narrowing, but can not differentiate fibrosis from inflammation. Capsule endoscopy and colonoscopy only see the superficial lumenal layer. The goal of this project is to develop diagnostic tools to detect enteric fibrosis in Crohn's disease, which will allow future work to determine which therapies are disease-modifying. We will study two new imaging modalities, computerized tomography enterography (CTE) and magnetic resonance enterography with magnetization transfer (MRE/MT). Our preliminary data suggest that CTE and MRE/MT are useful in assessing inflammation and fibrosis. MRE/MT specifically identifies changes in tissue stiffness, and may be able to quantitate collagen deposition in fibrotic tissue. This proposal will have three specific aims: 1) to evaluate the potential of MRE/MT to detect fibrotic tissue in rat models of Crohn's disease;2) to perform histologic correlation between CTE findings, MRE/MT findings, and tissue histology by studying patients prior to ileal resection;and 3) to perform a prospective longitudinal clinical study evaluating the ability of CTE and MRE/MT to detect changes in Crohn's disease over time and with therapy in a """"""""low fibrosis risk group"""""""" and a """"""""high fibrosis risk group"""""""" defined by NOD2 genotype. Our goal is to develop these two promising modalities to specifically detect tissue fibrosis. The information gained from CTE and MRE/MT will be immediately clinically useful for assessing disease activity and monitoring disease progression. MRE/MT has exciting potential for quantitating fibrosis, making it especially attractive for evaluating new therapeutic agents. Both of these tools will be clinically useful, and useful in clinical trials to monitor the progression of Crohn's disease. Lay description: Crohn's patients eventually develop bowel scarring and blockages that require surgery. It is impossible for physicians to detect scarring accurately without surgery. Our study aims to develop a way of detecting scarring without surgery, using state-of-the-art technology. This new test will change how patients are evaluated and will allow investigators to more accurately evaluate new medications for their ability to prevent fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073992-05
Application #
8142757
Study Section
Special Emphasis Panel (ZRG1-DIG-C (03))
Program Officer
Hamilton, Frank A
Project Start
2007-09-01
Project End
2012-12-30
Budget Start
2011-07-01
Budget End
2012-12-30
Support Year
5
Fiscal Year
2011
Total Cost
$298,184
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Reingold, Laura; Rahal, Kinan; Schmiedlin-Ren, Phyllissa et al. (2013) Development of a peptidoglycan-polysaccharide murine model of Crohn's disease: effect of genetic background. Inflamm Bowel Dis 19:1238-44
Rieder, Florian; Zimmermann, Ellen M; Remzi, Feza H et al. (2013) Crohn's disease complicated by strictures: a systematic review. Gut 62:1072-84
Adler, Jeremy; Rahal, Kinan; Swanson, Scott D et al. (2013) Anti-tumor necrosis factor ýý prevents bowel fibrosis assessed by messenger RNA, histology, and magnetization transfer MRI in rats with Crohn's disease. Inflamm Bowel Dis 19:683-90
Rahal, Kinan; Schmiedlin-Ren, Phyllissa; Adler, Jeremy et al. (2012) Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan-polysaccharide rat model of Crohn's disease. Inflamm Bowel Dis 18:613-23
Garcia, Patricia; Schmiedlin-Ren, Phyllissa; Mathias, Jason S et al. (2012) Resveratrol causes cell cycle arrest, decreased collagen synthesis, and apoptosis in rat intestinal smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 302:G326-35
Al-Hawary, Mahmoud; Zimmermann, Ellen M (2012) A new look at Crohn's disease: novel imaging techniques. Curr Opin Gastroenterol 28:334-40
Adler, Jeremy; Punglia, Darashana R; Dillman, Jonathan R et al. (2012) Computed tomography enterography findings correlate with tissue inflammation, not fibrosis in resected small bowel Crohn's disease. Inflamm Bowel Dis 18:849-56
Zimmermann, Ellen M; Al-Hawary, Mahmoud M (2011) MRI of the small bowel in patients with Crohn's disease. Curr Opin Gastroenterol 27:132-8
Adler, Jeremy; Swanson, Scott D; Schmiedlin-Ren, Phyllissa et al. (2011) Magnetization transfer helps detect intestinal fibrosis in an animal model of Crohn disease. Radiology 259:127-35

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