Necrotizing enterocolitis (NEC) is a severe, life threatening intestinal disorder of newborn infants with significant mortality and long term morbidity. Many factors have been implicated in the development of NEC; however, despite considerable attention the etiology of this disease remains unknown. Irrespective of etiology NEC is characterized by coagulative or ischemic necrosis of the mucosa occurring during the newborn period. This stage of normal human gastrointestinal development is characterized by considerable morphological remodeling and extensive changes in functional maturation of the gut mucosa. Thus, a resaonable conjecture is that functional immaturity of the intestine is a predisposing factor for developing NEC. The central hypotheses of this proposal are; 1) inadequate or altered mechanisms of injury-repair resulting from gastrointestinal immaturity predispose infants to necrotizing enterocolitis; and 2) that growth factor receptors belonging to the membrane-associated tyrosine kinase family are central regulatory molecules involved in the transduction of growth=regulatory and differentiation signals during normal intestinal morphogenesis, functional maturation and epithelial injury-repair. The long term objectives of this proposal are to determine the molecular mechanisms that regulate functional maturation and injury-repair in the developing gut and to identify the regulatory molecules that transduce growth and differentiation signals during gut development.
The specific aims of this proposal are; 1) to characterize changes in mucosal injury-repair that occur during perinatal intestinal development; 2) to determine the regional and cell-specific patterns of expression of gastrointestinal growth factor receptors during normal perinatal development of the gut epithelium; 3) to determine patterns of expression of gastrointestinal growth factor receptors during mucosal injury-repair. Developmental stage-specific differences in injury-repair will be investigated in rodent models systems of mucosal injury using morphological and functional markers of gastrointestinal differentiation. The regional and cell-specific patterns of expression will be determined for three gut-associated families of growth factor receptors during normal intestinal development. Expression of these growth factor receptors will be examined during injury-repair occurring at various developmental stages. The identification of the molecular mechanisms which regulate normal developmental maturation and injury-repair in the gut are likely to be central to progress in understanding the pathogenesis of NEC.
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