Michelle S. Longworth, PhD
Assistant Professor, Cellular and Molecular Medicinelongwom@ccf.org 216.444.8082 (o)
The long-term goal of the Longworth laboratory is to identify the mechanisms by which the organization and positioning of the global chromatin structure regulates transcription during development and in response to biological stress. The disorganization of chromatin and deregulation of transcription is implicated in a number of human diseases including cancers and developmental syndromes; our research is aimed at identifying novel pathways that could be targeted as drug therapies for diseases where chromatin organization is disrupted. Condensin II is a complex involved in organizing DNA at the global and local levels and in regulating transcription. Recently, we published that the transcriptional regulatory functions of CAP-D3, an essential subunit of Condensin II are necessary to clear intracellular bacteria in colon epithelial cells, and CAP-D3 levels are significantly lower in colon epithelial cells of patients with active Ulcerative colitis (UC), a type of Inflammatory Bowel Disease (IBD). Inflammatory Bowel Disease is a significant risk factor for development of colon cancer (Colitis Associate Cancer or CAC). Interestingly, we find that CAP-D3 deficiency during bacterial infections results in increased protein synthesis and increased cell cycling, suggesting that CAP-D3 may function to maintain cellular homeostasis during infection. We are currently researching the mechanisms and signaling pathways involved in this phenomenon. Additionally, we have continuing collaborations with the laboratories of 1) Dr. Christine McDonald to perform bacterial infections of cells, 2) Dr. Emina Huang to develop colon epithelial organoid cultures, and 3) Dr. Claudio Fiocchi to obtain IBD and CAC patient tissue samples for analysis in all of our studies. These combined factors uniquely position my lab to succeed in advancing our understanding of CAP-D3/Condensin II¿s potential roles in preventing Inflammatory Bowel Disease and CAC.