BILE ACIDS IN THE PATHOGENESIS OF NECROTIZING ENTEROCOLITIS

Project: Research project

Description

DESCRIPTION (provided by applicant): Necrotizing Enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. We have recently shown that accumulation of ileal bile acids (BAs) is a critical component of disease development in a neonatal rat model of NEC. The mechanism(s) for ileal BA accumulation have not been delineated; thus, the goal of this proposal is to clarify the mechanism(s) by which BAs accumulate and cause ileal tissue damage during experimental NEC. Data from our recent work suggests that alterations in ileal BA transport may play a crucial role in accumulation of ileal BAs during NEC pathogenesis. In Specific Aim 1, we will clarify the mechanisms by which ileal transport of BAs contributes to the accumulation of ileal BAs during experimental NEC in a neonatal rat model of NEC, in ileal BA transporter knockout mice with NEC, in ileal cell lines and in ileal explants from animals with NEC. Our preliminary data also show that levels of the sodium-dependent taurocholate transporting polypeptide (Ntcp) and the farnesoid x receptor (FXR) are significantly decreased in the liver of neonatal rats with NEC. In Specific Aim 2, we will explore both the production of BA in and transport of BA from the liver using the neonatal rat model of NEC, hepatic BA transporter transgenic mice, and primary hepatocyte cultures where crucial components of hepatic BA homeostasis are over expressed. BA can alter the intestinal environment to induce tissue injury. Our preliminary data show that the number of mucin positive intestinal epithelial cells (IEC) are significantly decreased and the levels of the TJ protein occludin are significantly increased in the ileum of rats with NEC. In Specific Aim 3, we will examine the mechanism(s) by which BAs contribute to ileal barrier dysfunction during NEC pathogenesis in neonatal rats with NEC, transgenic mice and in ileal cell lines and ileal explants. Data from the proposed studies will provide crucial understanding of the mechanisms involved in BA accumulation during experimental NEC as well as further delineate critical aspects of NEC pathogenesis. Clarification of the mechanisms involved in BA accumulation and BA-induced barrier dysfunction in experimental NEC will allow examination of BA homeostasis in human infants with this disease, and may ultimately lead to the use of elevated BAs as a predictive test of disease risk in the clinical setting.
StatusFinished
Effective start/end date9/20/076/30/13

Funding

  • National Institutes of Health: $314,458.00
  • National Institutes of Health: $366,251.00
  • National Institutes of Health: $314,458.00
  • National Institutes of Health: $351,600.00
  • National Institutes of Health: $320,875.00

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Necrotizing Enterocolitis
Bile Acids and Salts
Liver
Transgenic Mice
Homeostasis
Occludin
Cell Line
Taurocholic Acid
Gastrointestinal Diseases
Mucins

ASJC

  • Medicine(all)