Targeting Nuclear Receptors to Treat Fibrostenotic Crohn s Disease
Abstract
Crohn s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that are characterized by chronic inflammation in specific regions of the gastrointestinal tract, leading to extensive tissue damage and alterations in overall gut function. While some patients with IBD can be managed by existing therapies, a significant number of patients with CD and UC become unresponsive to drugs and manifest with severe disease complications often requiring surgical intervention. In patients with CD, severe and uncontrolled chronic intestinal inflammation can lead to structural changes in the gut wall and extreme narrowing of the intestine, a clinical term called stricturing. This type of CD, clinically referred to as fibrostenotic (fibro, referring to the structural changes; stenotic, referring to the narrowing of the intestine) disease, requires surgery to remove the damaged tissue. Intestinal stricture formation will occur in 30%-50% of CD patients within 10 years of disease onset. Unfortunately, more than 50% of those who undergo surgery to remove the damaged tissue will experience stricture recurrence. Despite significant advances in the treatment of CD, current therapies do nothing to target the biological pathways that contribute to stricture formation. It is currently thought that intestinal narrowing/stricture formation is driven by an abnormal response to inflammatory injury and alterations in the function of specific cell types within the intestinal wall. Interestingly, disease-related structural changes occur in other areas of the body, including the blood vessels, lungs, and kidneys, which are similar to those that occur in the intestine of CD patients. Many of the biological pathways that drive the structural changes in these tissues are similar, suggesting that common treatment targets may exist to treat inflammation-induced structural changes in disease. It was recently reported that the activation of NR4A1/Nur77, a receptor found in tissues of the blood vessels, lungs, and kidneys, could prevent disease-related structural changes. Interestingly, NR4A1/Nur77 is abundant in the intestine, but it is currently not known whether it serves a protective function in this system. To this end, the current proposal aims to determine whether NR4A1/Nur77 protects against disease-related structural changes in the gut and whether drugs that activate this receptor could be new treatments to block the inflammation-induced intestinal narrowing in fibrostenotic CD. Using cell-based systems, experimental animal models of CD and tissue isolated from patients, we will examine the role that NR4A1/Nur77 plays in the cells of the intestinal wall to discern whether its activation by pharmacological means could prove an effective treatment for fibrostenotic CD. The proposed studies constitute a novel area of IBD research whose findings could dramatically change clinical outcomes for fibrostenotic CD patients. The content is also well aligned with the "Inflammatory bowel diseases" topic outlined in the Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Areas. Should our studies indicate that NR4A1/Nur77 can protect against inflammation-induced intestinal narrowing, acts, they would constitute the first description of a therapy designed to specifically target the cells of the intestinal wall, a treatment method that would greatly reduce the frequency/severity of stricture formation and significantly decrease the requirement for surgical intervention in this patient population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610137
Entities
People
- Simon A Hirota
Organizations
- United States Army
- University of Calgary