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Research
Current Projects by Principal Investigator
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Research
Charalabos (Harry) Pothoulakis, MD
Professor of Medicine
Phone: 617-667-1259
Fax: 617-667-9144
Email: cpothoul@caregroup.harvard.edu
Curriculum Vita
Over the past few years our understanding of the pathophysiology of enterotoxin actions has evolved from a classic cell-oriented model to an integrated model incorporating neuronal and immune mediators in the lamina propria. A new paradigm of toxin-mediated intestinal secretion holds that the nervous system amplifies signals originating in the lumen when toxins stimulate epithelial cells. Our laboratory has incorporated this new model of toxin action into our studies of Clostridium difficile enterotoxin, the causative agent of antibiotic-associated colitis. C. difficile enterotoxin diarrhea is accompanied by considerable tissue necrosis and an intense acute neutrophilic infiltrate. Our laboratory showed for the first time that inflammatory diarrhea caused by C. difficile enterotoxin is controlled by sensory neurons containing the neuropeptides substance P and CGRP. Two other neuropeptides peptides, corticotropin-releasing hormone (CRH) and neurotensin are also involved in intestinal inflammation and secretion caused by this enterotoxin opening up the possibility for extensive communication between sensory neurons, neuroendocrine cells and enteric nerves in the pathophysiology of inflammatory diarrhea. Our studies also demonstrated that the mechanism by which some of these peptides mediate intestinal inflammation and secretion in the intestine is by interacting with specific receptors on epithelial cells as well as on immune and inflammatory cells of the intestinal lamina propria, including macrophages and mast cells. This notion has been recently extended in the pathophysiology of human disease as indicated by results from experiments using native human colon. These studies directly link the neuropeptides substance P and neurotensin with secretory responses in human colon. Recent results indicate also that the appetite suppressor hormone leptin is also a proinflammatory peptide involved in enterotoxin-mediated diarrhea and inflammation.
Ongoing studies in our laboratory are aimed in defining the molecular mechanism by which neuropeptides stimulate cells in the intestine and identify the specific signaling pathways that are activated in response to these peptides at the colonocyte level. We also showed a dramatic early increase in the expression of substance P, neurotensin, CRH, and leptin receptors in the intestine during the course C. difficile toxin - mediated intestinal inflammation. Studies underway in our laboratory are examining the mechanisms of upregulation of these receptors on intestinal epithelial cells and macrophages during intestinal inflammation.
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