The goal of the studies described in this proposal is the delineation of the role of peptide growth factors in mucosal repair after injury. Studies using simple in vitro models during the current support period have demonstrated that restitution, the initial stage of wound repair characterized by cellular migration to rapidly establish epithelial continuity, is controlled by several regulatory peptides, including both growth factors and cytokines. Importantly, all of these factors appear to act through transforming growth factor-beta (TGF-beta). Therefore, efforts under this proposal will focus on finding the mechanisms through which TGF-beta sustains the normal barrier and initiates restitution after injury followed by a proliferative response that reconstitutes the mucosal epithelial population. The goals of this proposal will be accomplished in three specific aims: 1). To determine the role of TFG-beta in maintaining the epithelial integrity and mucosal barrier function. This will be accomplished by using monolayers made unresponsive to TGF-beta through transfection with a """"""""dominant-negative"""""""" TGF-beta receptor and establishing a murine epithelial cell line by transgenic technology in which the epithelium has been made selectively unresponsive to TGF-beta in order to define the resulting effects on barrier function and wound healing. 2). To delineate the TFG-beta dependent mechanisms of restitution. Coordinate correlation of extracellular matrix and integrin receptors will be defined in conjunction with focal adhesion kinase and cytoskeletal structure after wounding to provide insight into the mechanisms which result in coordinate loss of cell priority and acquisition of a motile phenotype. 3). To delineate the mechanism downregulating the TGF-beta response to permit proliferative repair after restitution.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
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Massachusetts General Hospital
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Cario, E; Gerken, G; Podolsky, D K (2007) Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359-74
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Hisamatsu, Tadakazu; Suzuki, Manabu; Podolsky, Daniel K (2003) Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells. J Biol Chem 278:32962-8
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Cario, Elke; Brown, Dennis; McKee, Mary et al. (2002) Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol 160:165-73
Cario, E; Gerken, G; Podolsky, D K (2002) ""For whom the bell tolls!"" -- innate defense mechanisms and survival strategies of the intestinal epithelium against lumenal pathogens. Z Gastroenterol 40:983-90
Goke, M N; Cook, J R; Kunert, K S et al. (2001) Trefoil peptides promote restitution of wounded corneal epithelial cells. Exp Cell Res 264:337-44
Nishiyama, R; Sakaguchi, T; Kinugasa, T et al. (2001) Interleukin-2 receptor beta subunit-dependent and -independent regulation of intestinal epithelial tight junctions. J Biol Chem 276:35571-80
Cario, E; Podolsky, D K (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010-7
Podolsky, D K (2000) Review article: healing after inflammatory injury--coordination of a regulatory peptide network. Aliment Pharmacol Ther 14 Suppl 1:87-93

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