Unlike the full term vaginally delivered infant, the premature infant is unprepared to deal with initial colonizafion of the gut because of an underdeveloped mucosal immune system and thus is more suscepfible to age-related gastrointesfinal infiammatory diseases (e.g., necrofizing enterocolifis [NEC]). Accordingly a major research need is defining how these immaturities affect colonizing bacterial-intestinal """"""""crosstalk"""""""". We have studied immaturifies in intesfinal host defense using established in vitro and ex vivo human models of intesfinal development and have published that human fetal enterocytes respond with excessive (IL-8/IL-6) inflammafion to sfimuli (LPS, IL-1[3) and to both commensal and pathogenic bacteria. Recently we suggest that excessive inflammation may be due to a developmentally inappropriate expression of the enterocyte NFKB/MyD88 innate immune response genes and that intrauterine cortisone and postpartum probiofics may lessen the excessive IL-8 response by sfimulafing maturafion of these genes. Accordingly, our overall hypothesis is that inappropriate/immature enterocyte inflammafion in prematures after inifial bacterial colonizafion may be caused by a developmentally disrupted expression of innate immune response genes and may be prevented by the trophic factor corticosteroids (HC) and/or anti-inflammatory secreted factor(s) in probiofics. To address this hypothesis, we will confirm that fetal primary enterocyte inflammafion is due to a developmental expression of NFKB/MyD88 genes, determine if other inflammatory sfimuli (TNF-a, IL-1p) and inflammatory pathways (e.g., NFKB/TRIF, etc.) are affected and if other known negative regulators of inflammafion, sfimulated by commensal bacteria, are underexpressed. We will then determine if HC affects these developmentally underexpressed genes specifically or has a generalized effect on enterocyte development and if clinically-proven probiofic secrefions have an effect. This proposal in human models should provide the mechanisfic basis for excessive inflammation in prematures and in vitro evidence for prevenfion leading eventually to an acceptable regime for prevenfing NEC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK033506-27
Application #
8380327
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
27
Fiscal Year
2012
Total Cost
$269,974
Indirect Cost
$117,396
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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