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Research
Current Projects by Principal Investigator
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Research
Ciarán P. Kelly, MD
Associate Professor of Medicine
Phone: 617-667-1264
Fax: 617-975-5071
Email: ckelly2@bidmc.harvard.edu
Curriculum Vita
Fellows: Xinhua Chen
My research focuses on the pathogenesis of gastrointestinal infectious and inflammatory disorders. I have a longstanding interest in the host immune response to Clostridium difficile, the etiologic agent of antibiotic-associated diarrhea and pseudomembranous colitis (New Eng J Med, 1994;330:257-262).
My research has shown that a systemic humoral immune response to C. difficile toxin A is associated with natural protective immunity against C. difficile (New Eng J Med, 2000;342:390-397 & Lancet 2001;357:189-193). This important finding has opened the way to the development and testing of novel passive and active immunization regimens to prevent and treat C. difficile diarrhea and colitis. We have also shown that leukocyte activation by C. difficile toxins is an integral component of the pathophysiology of C. difficile enterocolitis (J Clin Invest 1994;1257-1265). We also find that the pro-inflammatory effects of C. difficile toxins result from the activation of NF-kB and MAP kinase signaling pathways by a mechanism independent of their previously described rho-glucosylation activity (J Clin Invest 2000;105:1147-1156).
In a second research project my laboratory examines the regulation of chemotactic cytokine (chemokine) gene expression in gastrointestinal epithelial cells. We have shown that contact with the gastric pathogen Helicobacter pylori activates MAP kinase and NF-kB signal transduction pathways in gastric epithelial cells leading to IL-8 gene transcription (Gastroenterology 1997:113;1099-1109). Furthermore, gene products encoded by the H. pylori cag pathogenicity island are required for NF-kB, p38 and JNK MAP kinase activation (J Immunol, 1999;163:5552-5559) and for gastric epithelial cell EGF receptor transactivation (J Biol Chem, 2001; 276:48127-48134). Infection by cag+ strains of H. pylori is associated with a greater risk for peptic ulcer disease and gastric cancer. Since the NFkB, MAP kinase and EGFR pathways regulate cell proliferation, differentiation, programmed death, stress and inflammatory responses their activation by H. pylori cag+ strains may be instrumental in the pathogenesis of gastroduodenal inflammation, ulceration and neoplasia.
I am actively involved in undergraduate medical education and, in addition to teaching on the clinical service, I am a Faculty member for a variety of ongoing HMS courses including: "Integrated Human Physiology", "Human Systems: Gastrointestinal Pathophysiology", "Core I, Medical Lecture Series", "Advanced Biomedical Science Course", and "Everything you always wanted to know from core medicine but were afraid to ask (HST 330)". I have been the Director of the 3-year, ACGME-approved, Gastroenterology Fellowship Training Program at BIDMC since 1997. In that role I coordinate the recruitment, clinical and research training and accreditation of 15 to 20 Gastroenterology trainees annually. In 2000, I was honored to assume the role of Chief of the Herrman L. Blumgart, Internal Medicine Firm. As Firm Chief I oversee the clinical training of Residents assigned to one of our four Internal Medicine firms, hold regular teaching ward rounds and run our weekly Firm Conference. Finally, I am a Faculty member for a variety of popular annual HMS, CME courses including "Update in Internal Medicine" and "Comprehensive Review of Gastroenterology".
I have served on grant review committees for the NIH, the Wellcome Trust (U.K.), The Health Research Board (Ireland) and for a number of local NIH-sponsored center grants. I served on the organizing committee of the 2004 NIH Consensus Development Conference on Celiac Disease. I am an active member of the American Gastroenterology Association and have assumed a number of leadership roles in that association (Chair of Abstract Review Committees, Chair of Clinical and Research Symposia, Councilor, Education Committee Member, Invited Speaker at Annual Meetings). My clinical activities are primarily in the subspecialty of Gastroenterology. I have special interests in the treatment of C. difficile colitis, inflammatory bowel disease, H. pylori gastritis, peptic ulcer disease, gastroesophageal reflux disease and gluten-sensitive enteropathy (celiac disease) and I have authored clinical review articles on these topics for major medical journals and textbooks.
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