The goal of this proposal is to elucidate the role of Paneth cell cryptdins in innate intestinal host defense. Disregulation of intestinal host defense mechanisms likely plays an important role in the pathophysiology of inflammatory bowel disease (IBD) and necrotizing eneterocolitis (NEC). Paneth cells, located at the base of intestinal crypts produce intestinal-specific alpha-defensins, termed cryptdins, which exhibit potent antimicrobial properties. We propose that Paneth cell cryptdins contribute to intestinal host defense by acting both as antimicrobial peptides and as paracrine pore-forming peptides to induce epithelial CI-secretory and IL-8 mediated proinflammatory responses.
The specific aims of this project are to: (i) define the mechanism of intestinal epithelial CI- secretion induced by Paneth cell secretions and granule contents (ii) explain how Paneth cell cryptdins induce a proinflammatory response from intestinal epithelial cells and (iii) examine the bioactivity of the human Paneth cell alpha-defensin HD-5. Studies proposed will utilize native murine cryptdins as Paneth cell secretions, synthesized and folded murine cryptdins, and recombinant human alpha-defensins. We will model cryptdin-epithelial interactions using the human intestinal cell line T84 and examine the mechanisms of cryptdin-induced CI- and IL-8 secretion. These studies will elucidate the role of cryptdins in intestinal host defense and innate immunity, and contribute to our understanding of the pathophysiology of many intestinal inflammatory disorders. The candidate's long-term career goal is to develop an academic career in neonatology with a basic research focus on gastrointestinal host defense mechanisms. {The rich environment provided by the support of her mentor, Dr. Andrew Neish, M.D. (Associate Professor in Pathology and Laboratory Medicine, Emory University Medical School), her co-mentor, Dr. Wayne Lencer, M.D. (Associate Professor in Pediatrics, Harvard Medical School), her advisory committee (Dr. Andre Ouellette, Ph.D., Professor in Pathology, University of California School of Medicine, Irvine, Dr. Sean Colgan, Ph.D., Associate Professor in Anesthesia, Harvard Medical School, and Dr. Charles Parkos, M.D., Ph.D., Associate Professor in Pathology and Laboratory Medicine, Emory University Medical School), her collaborators, and Emory University School of Medicine will provide the resources necessary to help her achieve her objectives.
| Lin, Patricia W; Nasr, Tala R; Berardinelli, Andrew J et al. (2008) The probiotic Lactobacillus GG may augment intestinal host defense by regulating apoptosis and promoting cytoprotective responses in the developing murine gut. Pediatr Res 64:511-6 |
| Zeng, Hui; Wu, Huixia; Sloane, Valerie et al. (2006) Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am J Physiol Gastrointest Liver Physiol 290:G96-G108 |
| Lin, Patricia W; Simon Jr, Peter O; Gewirtz, Andrew T et al. (2004) Paneth cell cryptdins act in vitro as apical paracrine regulators of the innate inflammatory response. J Biol Chem 279:19902-7 |
