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 #
5P01DK033506-29
Application #
8727514
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Hamilton, Frank A
Project Start
1997-04-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
29
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Senger, Stefania; Ingano, Laura; Freire, Rachel et al. (2018) Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC). Cell Mol Gastroenterol Hepatol 5:549-568
Henström, Maria; Diekmann, Lena; Bonfiglio, Ferdinando et al. (2018) Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut 67:263-270
Guo, Shuangshuang; Gillingham, Tyler; Guo, Yuming et al. (2017) Secretions of Bifidobacterium infantis and Lactobacillus acidophilus Protect Intestinal Epithelial Barrier Function. J Pediatr Gastroenterol Nutr 64:404-412
Walker, W Allan (2017) The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health. Pediatr Res 82:387-395
Hoffman, Jill M; Baritaki, Stavroula; Ruiz, Jonathan J et al. (2016) Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. Am J Pathol 186:134-44
Meng, Di; Zhu, Weishu; Ganguli, Kriston et al. (2016) Anti-inflammatory effects of Bifidobacterium longum subsp infantis secretions on fetal human enterocytes are mediated by TLR-4 receptors. Am J Physiol Gastrointest Liver Physiol 311:G744-G753
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
Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang et al. (2016) A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun 7:12225
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
Rautava, Samuli; Walker, W Allan; Lu, Lei (2016) Hydrocortisone-induced anti-inflammatory effects in immature human enterocytes depend on the timing of exposure. Am J Physiol Gastrointest Liver Physiol 310:G920-9

Showing the most recent 10 out of 271 publications