Epithelial Tissue Mechanics: A New Key to Relapse in Chronic Inflammatory Bowel Disease
Abstract
Peer Reviewed Medical Research Program (PRMRP) Portfolio: Autoimmune Disorders and Immunology; Fiscal Year 2022 (FY22) PRMRP Topic Area: Inflammatory Bowel Disease; FY22 PRMRP Strategic Goal: Foundational Studies – Identify factors, to include environmental exposures, lifestyle triggers, and past medical history, impacting the onset and progression of associated immune- mediated diseases Rationale: Crohn’s disease and ulcerative colitis are inflammatory bowel diseases (IBD) that are often diagnosed in otherwise healthy people in their twenties and thirties; carry symptoms that are painful, embarrassing, and debilitating; and characteristically have a chronic course, distinguished by periods of relapse and remission. IBD is a medical bar to joining the military, and its unpredictable symptoms often prevent patients from serving active roles. IBD is a priority area for the military, since several factors associated with military service can increase the chances of developing this condition, including the stress of intensive training, gut infections, and psychological stress. IBD also affects Veterans and the dependents of Service people, creating a burden for the Department of Veterans Affairs (VA) health system. A major goal of therapy is to prevent IBD from relapsing and thus prolong disease-free remission. At the present time, such therapies are based on the idea that low-grade inflammation occurs in the gut of IBD patients, even when they appear to be in remission. This low-grade inflammation then triggers the development of full-blown disease. Therefore, measures to prevent relapse include the use of agents directed against that low-grade, subclinical inflammation. However, these approaches are not ideal. Specific biological agents directed against the inflammatory process often wear off after time; and less-specific anti-inflammatory drugs (such as steroids) carry significant side effects. There is a clear need for new approaches that would help prevent relapse and prolong the disease-free periods for IBD patients. Hypothesis and Aims: This proposal tests a new concept for how subclinical inflammation may provoke overt disease. Based on our pilot findings, we propose that the inflammatory factors produced during subclinical disease (i.e., even in remission) alter the mechanical properties of the lining of the gut (the epithelium). This mechanical change prevents the gut lining from eliminating dying cells. Importantly, cell death is a common, normal feature in the gut, which usually does not cause any problems, because dying cells are readily eliminated. However, if they cannot be eliminated, dying cells can themselves provoke inflammation; we propose that these retained dying cells are critical for provoking IBD relapse. These findings carry the implication that correcting tissue mechanics may reduce the risk of the disease breaking out, even though low-grade inflammation may persist. In this Discovery Award, we seek to test this idea using animal models of IBD. We will test how the mechanical properties of the gut are altered as inflammation develops, even before disease breaks out, and how drugs that correct abnormal mechanics may delay or prevent the onset of full-blown disease. Impact: If successful, this project will establish a new way for us to understand what causes IBD relapse, new knowledge that can lead to new types of treatments to prevent relapse. The long-term aim of this work is the potential to use new drugs that correct gut tissue mechanics to help prevent or delay the relapse of IBD. These drugs act on the skeleton of cells and therefore are independent of conventional immune-based treatments designed to reduce low-grade inflammation. Thus, these drugs could be used as alternatives or in combination with current immune therapies, to prolong disease-free life of patients with IBD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310088
Entities
People
- Alpha Yap
Organizations
- United States Army
- University of Queensland