ROLE OF TRANSFORMING GROWTH FACTOR-BETA IN NEONATAL NECROTIZING ENTEROCOLITIS
Akhil Maheshwari, Assistant Professor
University Of Alabama At Birmingham, 1530 3rd Avenue South, Birmingham, Al 35294
Grant 5R01HD059142-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Necrotizing enterocolitis (NEC) is an acquired, life-threatening gastrointestinal disease affecting 5-15% of neonates born weighing less than 1500 g and is a leading cause of death in these patients. The disease is characterized by an intense inflammatory response, ischemic changes, and necrosis. Although the etiopathogenesis of NEC is not well understood, the disease is believed to occur when mucosal injury or altered permeability allows bacterial translocation into the lamina propria, causing leukocyte recruitment and tissue destruction. This model of unrestricted acute inflammation due to bacteria/bacterial products is inconsistent with recent observations that in the adult, intestinal cells such as macrophages are profoundly
Relevance: anergic´ to bacterial products due to the effect of stromal cell-derived factors such as transforming growth factor (TGF)-2. The investigators present preliminary data and propose a novel hypothesis that NEC is seen almost exclusively in the premature infant because mucosal tolerance to bacterial products, which is due to the effects of TGF-2, is developmentally regulated and therefore deficient in the preterm intestine, and that augmentation of TGF-2 expression or bioactivity can prevent/ameliorate NEC-like intestinal injury. This application is designed to investigate strategies to augment TGF-2 activity in the developing intestine in order to enhance mucosal tolerance to bacterial products. There are three specific aims: 1) to determine whether specific patterns of bacterial colonization of the neonatal intestinal mucosa affect the normal developmental downregulation of inflammatory pathways in the intestinal mucosa or influence susceptibility to NEC-like intestinal injury; 2) to determine the role of milk-borne TGF-22 in protection against NEC-like intestinal injury, and whether enteral supplementation of TGF-22 in the neonate can provide additional protection against NEC-like intestinal injury; and 3) to determine whether pharmacological upregulation of TGF-22 expression or activation in the developing intestine can protect against NEC-like intestinal injury. The long-term goals of this project are to identify newer preventive/therapeutic strategies against NEC that can be tested in future clinical studies. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely premature infants. In this application, the investigators present a novel hypothesis that NEC occurs almost exclusively in premature infants because normal tolerance to gut bacteria is not yet established in these infants and propose three different strategies to correct this deficiency, which can, in turn, help prevent or treat NEC
Project start date: 2009-02-28
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: http://Excellgen.com
Akhil Maheshwari
University Of Illinois At Chicago
Project start date: 2009-02-28
Project end date: 2014-01-31
Grants awarded to Akhil Maheshwari
ROLE OF TRANSFORMING GROWTH FACTOR-BETA IN NEONATAL NECROTIZING ENTEROCOLITIS
Akhil Maheshwari, Assistant Professor
University Of Alabama At Birmingham, 1530 3rd Avenue South, Birmingham, Al 35294
Grant 3R01HD059142-01S1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This award is issued in response to Notice OD-09-060, Recovery Act Administrative Supplements Providing Summer Research Experiences for Students and Science Educators. Necrotizing enterocolitis (NEC) is an acquired, life-threatening gastrointestinal disease affecting 5-15% of neonates born weighing less than 1500 g and is a leading cause of death in these patients. The disease is characterized by an intense inflammatory response, ischemic changes, and necrosis. Although the etiopathogenesis of NEC is not well understood, the disease is believed to occur when mucosal injury or altered permeability allows bacterial translocation into the lamina propria, causing leukocyte recruitment and tissue destruction. This model of unrestricted acute inflammation due to bacteria/bacterial products is inconsistent with recent observations that in the adult, intestinal cells such as macrophages are profoundly
Relevance: anergic´ to bacterial products due to the effect of stromal cell-derived factors such as transforming growth factor (TGF)-2. The investigators present preliminary data and propose a novel hypothesis that NEC is seen almost exclusively in the premature infant because mucosal tolerance to bacterial products, which is due to the effects of TGF-2, is developmentally regulated and therefore deficient in the preterm intestine, and that augmentation of TGF-2 expression or bioactivity can prevent/ameliorate NEC-like intestinal injury. This application is designed to investigate strategies to augment TGF-2 activity in the developing intestine in order to enhance mucosal tolerance to bacterial products. There are three specific aims: 1) to determine whether specific patterns of bacterial colonization of the neonatal intestinal mucosa affect the normal developmental downregulation of inflammatory pathways in the intestinal mucosa or influence susceptibility to NEC-like intestinal injury; 2) to determine the role of milk-borne TGF-22 in protection against NEC-like intestinal injury, and whether enteral supplementation of TGF-22 in the neonate can provide additional protection against NEC-like intestinal injury; and 3) to determine whether pharmacological upregulation of TGF-22 expression or activation in the developing intestine can protect against NEC-like intestinal injury. The long-term goals of this project are to identify newer preventive/therapeutic strategies against NEC that can be tested in future clinical studies. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely premature infants. In this application, the investigators present a novel hypothesis that NEC occurs almost exclusively in premature infants because normal tolerance to gut bacteria is not yet established in these infants and propose three different strategies to correct this deficiency, which can, in turn, help prevent or treat NEC
Project start date: 2009-06-01
Project end date: 2010-10-31
Budget start date: 1-JUN-2009
Budget end date: 31-OCT-2010
