Antibacterial Functions of CAP-D3/Condensin II in the Colonic Epithelium
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn s disease (CD), is a devastating illness characterized by chronic inflammation of the gastrointestinal tract with periods of remission and relapse. There is currently no cure for IBD, and it affects over 1.4 million people in the United States, resulting in an annual financial burden that is estimated to be greater than $30 billion. While the average age at diagnosis is approximately 30 years of age, IBD affects all ages and there may be as many as 80,000 children in the United States with IBD. Additionally, IBD is a significant risk factor for the development of colitis-associated cancer, a type of colon cancer. The cause of IBD is thought to be multifactorial. One factor known to contribute to the development of IBD and to exacerbate inflammation in the intestine is prior and/or chronic bacterial infection. The intestine contains a layer of "epithelial" cells that act as the first line of defense against bacteria and physically separate bacteria from immune cells. Upon bacterial infection, epithelial cells employ mechanisms to quickly and efficiently destroy bacteria to prevent them from replicating and spreading to other cells. Importantly, if epithelial antibacterial defenses are defective, this can result in chronic bacterial infection and prolonged host responses involving severe inflammation that damages the tissue. Defects in the antibacterial defenses of the colon epithelial cells are associated with UC. However, a complete understanding of all of the proteins involved in promoting bacterial clearance and thus preventing chronic infection in colon epithelial cells is lacking. Our lab recently identified a novel role for the CAP-D3 (Chromosome Associated Protein-D3) protein in promoting bacterial clearance in colon epithelial cells through its ability to regulate gene expression (turn genes on and off). Excitingly, CAP-D3 protein levels are significantly lower in colon epithelial cells isolated from UC patients with active disease in comparison to cells from patients not diagnosed with IBD. This means that in the colon, epithelial cells of UC patients exhibiting high levels of inflammation, the lower levels of CAPD3 may promote chronic bacterial infections, leading to increased inflammation, which could lead to disease relapse. Therefore, this proposal aims to discover how CAP-D3 regulates genes during bacterial infection in colon epithelial cells and how this might preserve normal functions in the cells so that they can adequately respond to infection without adverse consequences. Excitingly, we recently also discovered that colon epithelial cells from a significant percentage of IBD patients, including those diagnosed with colitis associated cancer, harbor a previously unidentified, smaller form of CAP-D3 protein that is not expressed in any of our non-IBD patient samples. Therefore, we will also study how this smaller CAP-D3 protein is formed and whether it is deficient in its ability to regulate genes and prevent chronic infection. Completion of these aims will uncover new pathways whose dysfunction may result in chronic bacterial infection in the colonic epithelium, and which could be targeted with novel therapeutics aimed at preventing development and/or relapse of IBD. In addition, these studies may identify the smaller CAP-D3 protein as a good candidate for a biomarker to be used in the diagnosis of IBD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610355
Entities
People
- Michelle S Longworth
Organizations
- Cleveland Clinic
- United States Army