Cytoplasmic Suppression of Inflammatory Signaling
Abstract
Topic Area: This project addresses the Discovery Award Topic Area of inflammatory bowel disease (IBD). It investigates how a protein called ABIN-1 works to repress inflammatory signals that if left unchecked can damage and ultimately kill intestinal cells. As some of these inflammatory signals come from breakdown products shed by gut bacteria, it also addresses the Area of Encouragement of understanding how acute bowel infections may trigger IBD. Overview: Initiation and progression of IBD are likely caused by interaction among multiple exacerbating factors such as genetics, poor quality diet, imbalanced gut bacteria, and environmental hazards, physical and psychological stress. The last four are likely of particular significance for deployed personnel as opposed to civilian populations. Nevertheless, all or some of these may combine as a “perfect storm” to overwhelm an intestinal cell’s ability to limit response to an incoming inflammatory signal. This leads to tissue damage leading to cellular debris leading to more inflammation and excessive responses recognized as IBD. Successful clinical intervention requires stopping or at least significantly limiting this cascade of inflammatory signals. Despite some disease management with anti-inflammatory drugs (e.g., corticosteroids and immune cell anti-metabolite compounds) and signal blocking biologics (antibodies), upwards of 20% of patients may ultimately require surgery. The US Department of Health reported in 2018 about 3.1 million US adults have IBD; disease incidence and prevalence are increasing. Treatment costs along with lost income and workplace productivity are estimated to total $12-$31 billion annually in the US. These personal and societal costs mandate new understanding of proteins involved in IBD to identify them as potentially new drug targets. Research Description: IBD has hallmarks of intestinal cell dysfunction/death and tissue inflammation from infiltrating immune cells. However, there remains significant gaps in understanding the inflammation-related signaling that occurs within intestinal epithelial cells damaging them even without immune cell involvement. Anti-inflammatory proteins within intestinal cells may be key to new therapies. ABIN-1 protein is a brake on IBD-associated inflammatory signals (like bacteria and gut cell debris) coming through the intestinal cell membrane. Unchecked, these signals activate intracellular relay proteins ultimately activating gene expression damaging and sometimes killing the intestinal cell. Unlike the interactions of rigid lock-and-key type proteins, this project proposes ABIN-1 protein is a “shape-shifter” and that only one shape is able to interact with the partner protein needed to successfully block inflammatory signals. This is consistent with reports that ABIN-1 is quickly broken down in cells activated by inflammatory signals, possibly because its constantly changing shape “opens” it up to easier attack by degradative enzymes. Our long-term goal is identification of new drugs that could chaperone ABIN-1 to the shapes recognized by its partner anti-inflammatory proteins, protecting it from degradation and enhancing its capacity to block incoming signals. To reach that point, the immediate aims of this proposal are (i) to predict and test ranges of shape and degrees of flexibility for ABIN-1 protein using computer analysis of its amino acids, (ii) to assess standard and variant ABIN-1 protein for ranges of shape and degrees of flexibility using established test tube-based protein shape detection and stability techniques, and (iii) to generate standard and variant sequence ABIN-1 protein within human cells in petri dishes to test for its inflammatory signal braking when those cells are exposed to laboratory examples of bacterial and gut cell debris. This integrated approach is expected to cross-check the preliminary studies further testing the interpretation that ABIN-1 has protein qualiti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010081
Entities
People
- Brian Aneskievich
Organizations
- United States Army
- University of Connecticut