This Program Project renewal application continues to have a narrow focus on the role of enterocytes in mucosal barrier function at the interface between microbial and enterotoxin-mediated stimuli and immune effector responses. The enterocyte is the central focus and will be studied with regard to microbial """"""""crosstalk"""""""" and immune-epithelial cell interactions, neuropeptide receptor expression, inappropriate developmental responses, and a barrier to microbial penetration. This renewal application consists of five interactive projects supported by two cores, (1) An Administrative and (2) a Xenograft/lsograft Transplant, human intestinal tissue and imaging core principally in one location in the Mucosal Immunolog Laboratory at the Massachusetts General Hospital-East (BIdg 114). Project 1 will examine immaturities in NFkappaB/MyD88 innate response genes and in other inflammatory pathways in fetal vs. mature enterocytes to help explain excessive intestinal inflammation in prematures and test maturational prevention with hydrocortisone and probiotics. Project 2 will examine the mechanisms involved in the participation of corticotropin-releasing hormone family of neuropeptides and their receptors in the development of mucosal inflammation in response to enterotoxiris and bacterial pathogens. Project 3 will study the molecular mechanisms underiying S. flexneri-intestinal epithelial interactions at the apical or basolateral membrane domain that lead to acute infectious colitis. Project 4 will determinethe role of GEF-H1, a guanine nucleotide exchange factor (GEF) for Rho, on epithelial cell responses to pathogens and examine the mechanism of this response at the tight junctional level. Project 5 will define specific cellular and molecularmechanisms involved in the protective and therapeutic effects of the probiotic agent .S.boulardii in enteric infections and enterotoxin-mediated diarrhea and intestinal.inflammation. Investigators.with disciplines in cell/molecular biology,,microbiology, intestinal immunity and inflammation.cand developmental biology will provide a better understanding of the pathogenesis of bacterial Gl infections and enterotoxin-mediated intestinal inflammation and niay lead to new therapeutic strategies in preventing and treating infectious diseases in the Gl tract.

Public Health Relevance

This Program Project examines how colonizing bacteria stimulate intestinal host defense and prevents inflammation by pathogens and their toxins as a translation contribution. Observations made may lead to strategies for prevention of intestinal infectious disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK033506-28
Application #
8545570
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Hamilton, Frank A
Project Start
1997-04-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
28
Fiscal Year
2013
Total Cost
$1,352,473
Indirect Cost
$445,937
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Giannogonas, Panagiotis; Apostolou, Athanasia; Manousopoulou, Antigoni et al. (2016) Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy. Sci Rep 6:23342
Gregory, Katherine E; Samuel, Buck S; Houghteling, Pearl et al. (2016) Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome 4:68
Saslowsky, David E; Thiagarajah, Jay R; McCormick, Beth A et al. (2016) Microbial sphingomyelinase induces RhoA-mediated reorganization of the apical brush border membrane and is protective against invasion. Mol Biol Cell 27:1120-30
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O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4
Zhou, Yanjiao; Shan, Gururaj; Sodergren, Erica et al. (2015) Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS One 10:e0118632
Walker, W Allan; Iyengar, Rajashri Shuba (2015) Breast milk, microbiota, and intestinal immune homeostasis. Pediatr Res 77:220-8
Ganguli, Kriston; Collado, Maria C; Rautava, Jaana et al. (2015) Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut. Pediatr Res 77:528-35
Meng, Di; Zhu, Weishu; Shi, Hai Ning et al. (2015) Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis. Pediatr Res 77:416-24

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