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ARRA Investments in Inflammatory Bowel Diseases


Public Health Burden
Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, are marked by chronic and destructive inflammation in the intestinal tract.  The precise causes of IBD are unknown, and, while a variety of medications are available to control the symptoms of IBD, there is currently no cure.  To better understand the cause(s) of IBD and accelerate the development of new therapeutic strategies, scientists are dissecting the genetic, cellular, and environmental factors that might contribute to its development.

Genetics of IBD
The NIH established the IBD Genetics Consortium to accelerate the discovery of genetic variations that are associated with the disease.  To date, IBD-associated variations have been identified in over 30 genetic regions.  A number of ARRA awards have been made to identify additional genetic variations and understand how they contribute to IBD:
  • Additional funding awarded to Genetic Research Centers of the IBD Genetics Consortium will enhance its ability to expand and develop resources and identify additional genetic variations that contribute to IBD susceptibility.1,2,3
     
  • A study will identify genetic variations that are less common amongst patients with Crohn’s disease, providing additional insight on the causes of disease and the responsiveness of select patient populations to potential therapies.4
  • Researchers are investigating the diversity of genes and genetic variations that predispose individuals from different ethnic groups to developing IBD.5,6
  • By defining the biological processes that are perturbed by genetic variations associated with IBD, researchers will be able to assess how particular genes influence the risk of developing IBD.7
Mechanisms of Chronic Inflammation in the Intestines
The mechanism(s) by which chronic inflammation occurs in the intestines of people with IBD is unknown.  In order to better understand what triggers the onset and progression of IBD, ARRA has provided funding to researchers studying the biological processes involved in the intestinal inflammatory response and how they go awry in IBD:
  • Researchers are investigating how the network of molecules on the surface of cells lining the intestines is altered in IBD, and how these changes enhance the recruitment of immune cells to generate a recurrent inflammatory state.8
  • A project will examine how a cellular protein—orphan nuclear receptor Nur77—regulates the formation of blood vessels in the intestine to increase delivery of immune cells and modulate the inflammatory response in colitis.9
  • Since chronic inflammation in IBD may be triggered by the inappropriate activation of immune cells in response to bacteria that naturally reside in the intestine, researchers are studying how a protein—intestinal alkaline phosphatase—acts as an anti-inflammatory factor to promote tolerance of non-pathogenic gut microbes.10
  • Researchers are also investigating the role of another key cellular signaling molecule—nuclear factor kappa-B (NF-kappaB)—in driving the pathologic inflammation associated with IBD in response to resident bacteria of the intestines.11
Role of the Intestinal Barrier in IBD
The cells lining the intestines form a protective barrier that prevents contents of the intestine from reaching underlying tissue layers.  Since defects in barrier function have been associated with IBD, researchers are studying the factors that contribute to normal barrier function in order to understand how their dysfunction contributes to disease.  ARRA-funded grants studying the intestinal barrier will:
  • Investigate how a small molecule—s-nitrosoglutathione—regulates the function of the intestinal barrier by modifying the proteins that hold together the cells lining the intestine.12
  • Determine how a family of proteins known as junction adhesion molecules maintains intestinal barrier integrity and regulates the ability of immune cells to cross the barrier and modulate the inflammatory response.13
IBD Treatments and Diagnostics
Although there is currently no cure for IBD, previous investments in understanding fundamental aspects of intestinal biology have paved the way for developing and testing new therapeutic and diagnostic strategies.  ARRA investments in novel treatments and diagnostics for IBD include:
  • The development and testing of nanoscale-particles that deliver drugs specifically to inappropriately-activated immune cells within the intestine and turn off inflammation in mouse models of colitis.14
  • The continued development of non-invasive approaches for diagnosing intestinal fibrosis in IBD, which will allow researchers to determine which therapies not only mitigate inflammation but also modify the course of disease progression.15



  1. 3U01DK062420-08S1 -- NIDDK IBD Genetics Consortium Genetic Research Center --Duerr, Richard H (PA)
  2. 3U01DK062422-09S1 -- Yale University IBD Genetics Research Center -- Cho, Judy H (CT)
  3. 3U01DK062429-09S1 -- IBD Genetics Consortium Data Coordinating Center -- Cho, Judy H (CT)
  4. 1RC1DK086800-01 -- Beyond Single-Point GWAS: Genetics of Crohn’s Disease in Ashkenazi Jews -- Cho, Judy H (CT)
  5. 1R01DK083553-01 -- Identifying Disease Variants for Familial Crohn’s Disease -- Brant, Steven R (MD)
  6. 3U01DK062431-08S1 -- IBD Gene Mapping by Clinical and Population Subsets -- Brant, Steven R (MD)
  7. 1RC1DK086502-01 -- Genetics, Genes, and Pathways in Inflammatory Bowel Disease (IBD) -- Daly, Mark J (contact); Xavier, Ramnik J (MA)
  8. 2R01DK054213-10A1 -- Extracellular matrix in inflammatory bowel disease -- Levine, Alan David (OH)
  9. 1R21DK080970-01A2 -- Orphan Nuclear Receptor Nur77 and Intestinal Inflammation -- Zhao, Dezheng (MA)
  10. 3R01DK075549-03S2 -- Molecular Basis of Host-Microbiota signaling in the Zebrafish Gut -- Guillemin, Karen J (OR)
  11. 2R01AI052267-06A2 -- Inhibition of Microflora-induced Colitis by NF-kappaB -- Horwitz, Bruce H (MA)
  12. 1R21DK078032-01A2 -- S-nitrosoglutathione regulation of intestinal barrier function in Crohn’s disease -- Savidge, Tor (TX)
  13. 3R01DK072546-15S1 -- Neutrophil Interactions with Intestinal Epithelial Cells -- Parkos, Charles A (GA)
  14. 1RC1DK087348-01 -- Targeted siRNA Delivery to Aberrantly Activated Leukocytes for Treating Colitis -- Shimaoka, Motomu (MA)
  15. 3R01DK073992-02S1 -- Detection of inflammation versus intestinal fibrosis in Crohn’s Disease -- Zimmermann, Ellen M (MI)


 
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