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Atsushi
Mizoguchi, MD, PhD
Assistant Professor
Harvard Medical School
Assistant Immunologist
Molecular Pathology Unit
Massachusetts General Hospital
149, 13th Street, Room 6024
Charlestown, MA 02129
Phone: 617-726-8492
Fax: 617-726-5684
Email: amizoguchi@partners.org |
Affiliations: Center
for the Study of Inflammatory Bowel Disease
Research Interests:
Inflammatory bowel disease (IBD) is a group of chronic, relapsing and remitting inflammatory conditions that affect individuals throughout the life. My laboratory has focused on the studies to provide rationales to develop novel therapeutic strategies for IBD patients by utilizing genetically engineered experimental models of this disorder. In addition to research activity, I have served as Editorial Board Members in Gastroenterology, Journal of Immunology, and Journal of Gastroenterology.
Although autoimmune mechanisms are involved in the pathogenesis of IBD, it is not known whether intestinal epithelial cell-derived antigens (self-antigens) are involved in this process. To address this issue, we performed serological analysis of recombinant cDNA expression libraries (SEREX) and have unexpectedly identified an epithelial cell-derived lectin, galectin-4, as a stimulator of colitogenic CD4+ T cells. This discovery has provided us an unexpected opportunity to more closely examine the mechanism by which pathogenic CD4+ T cells are further activated under intestinal inflammatory conditions. Galectin-4, which interacts with sugar (a core 1 composition of O-glycan), contributes to the exacerbation of colitis by cross-linking certain glycoreceptors within immunological synapse on the pathogenic CD4+ T cells that are present in inflamed, but not normal, colon. This galectin-4 binding stimulates the CD4+ T cells to produce IL-6 through the activation of protein kinase C-theta-associated signaling cascade. My laboratory is currently focusing on the study to identify the distal and proximal signaling cascades that are activated by the galectin-4 and to define the specific glycosylational changes that allow CD4+ T cells to interact with galectin-4 under intestinal inflammatory conditions. This project has been supported by NIH RO1 grant.
Dysregulated host/microbial interaction is required for the development of IBD. Intestinal epithelial cells, which provide a first defense line against enteric microorganisms, have been considered to play a critical role for maintaining the appropriate host/microbial interaction. To strengthen the epithelial barrier function, an activation of signal transducer and activator of transcription (STAT) 3 is required. Recently, we have found that IL-22 (a recently identified cytokine of IL-10 family) is specifically expressed under intestinal inflammatory condition and subsequently contributes to the attenuation of ulcerative colitis (UC)-like disease by specifically activating the STAT3 cascade in the epithelial cells. Therefore, we hypothesize that further enhancement of IL-22 production may be beneficial to improve the life of patients with UC. A study using a novel, non-viral mediated local gene delivery system to supplement IL-22 expression in the inflamed colon is currently conducted to test our hypothesis. This project has been supported by The Eli and Edythe L. Broad Foundation.
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