Abstract

The proposed studies are designed to test the hypothesis that Necrotizing Enterocolitis (NEC) is a disease of immature intestinal host defense triggered by the introduction of artificial feedings and propagated by an inappropriate microbial colonization and enterocyte response. To test this hypothesis, the P.I. will study human fetal in vitro intestinal models by further characterizing an established human intestinal non-malignant epithelial cell line as to the function (including receptor expression, signal transduction and effector response), microenvironmental factors affecting differentiation and using SV-40 large T antigen construct to immortalize these cells. The P.I. will also study initial bacterial colonization of the human gut and define immaturities of bacterial- enterotoxin """"""""crosstalk"""""""" including adherence, colonization and translocation of pathologic bacteria, mechanisms of glycosyltransferase activity leading to colonization, endotoxin-immature enterocyte interaction as well as the ontogeny of Paneth cell cryptdin expression.
The final aim i s designed to use human in vitro intestinal models to study mechanisms for strategies to prevent pathologic bacterial colonization.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD031852-08
Application #
6387649
Study Section
Special Emphasis Panel (ZRG2-RAP (02))
Program Officer
Grave, Gilman D
Project Start
1994-05-01
Project End
2004-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
8
Fiscal Year
2001
Total Cost
$310,300
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Lu, Lei; Bao, Yuanwu; Khan, Abdullah et al. (2008) Hydrocortisone modulates cholera toxin endocytosis by regulating immature enterocyte plasma membrane phospholipids. Gastroenterology 135:185-193.e1
Savidge, Tor C; Newman, Paul; Pothoulakis, Charalabos et al. (2007) Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132:1344-58
Meng, Di; Newburg, David S; Young, Cheryl et al. (2007) Bacterial symbionts induce a FUT2-dependent fucosylated niche on colonic epithelium via ERK and JNK signaling. Am J Physiol Gastrointest Liver Physiol 293:G780-7
Chen, Chien-Chang; Louie, Steve; McCormick, Beth A et al. (2006) Helminth-primed dendritic cells alter the host response to enteric bacterial infection. J Immunol 176:472-83
Nanthakumar, N Nanda; Dai, Dingwei; Meng, Di et al. (2005) Regulation of intestinal ontogeny: effect of glucocorticoids and luminal microbes on galactosyltransferase and trehalase induction in mice. Glycobiology 15:221-32
Nanthakumar, N Nanda; Young, Cheryl; Ko, Jae Sung et al. (2005) Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 288:G85-92
Yuan, Qian; Walker, W Allan (2004) Innate immunity of the gut: mucosal defense in health and disease. J Pediatr Gastroenterol Nutr 38:463-73
Shi, Hai Ning; Walker, Allan (2004) Bacterial colonization and the development of intestinal defences. Can J Gastroenterol 18:493-500
Huang, Fu-Chen; Werne, Adam; Li, Qian et al. (2004) Cooperative interactions between flagellin and SopE2 in the epithelial interleukin-8 response to Salmonella enterica serovar typhimurium infection. Infect Immun 72:5052-62
Claud, Erika C; Lu, Lei; Anton, Pauline M et al. (2004) Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci U S A 101:7404-8

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