Recent epidemiological data indicate intrahepatic cholestasis of pregnancy (ICP) has an incidence of between 1.5-4% and is related to serum bile acid concentrations. While the health problem for the mother can be resolved, fetal and post-natal complications frequently lead to untoward consequences to the infant including mortality related to respiratory distress. There are significant gaps in our knowledge of the genetic factors that cause ICP. Our preliminary studies with a mouse lacking the hepatic bile salt export protein (Abcb11 aka Bsep, a member of the ATP binding cassette superfamily) indicated that this mouse knockout developed progressive cholestasis thereby recapitulating, for the first time the phenotype of humans with ABCB11 deficiency. More importantly, dams lacking Abcb11 have high concentrations of bile acids during pregnancy and 100% of the neonatal mice die within 24h of postnatal respiratory distress. Our main hypothesis for these exploratory studies is that elevated maternal bile acids disrupt normal development and maturation of fetal lungs. These exploratory studies reveal a genetic mechanism showing maternal insufficiency in Abcb11 as a potent risk factor for neonatal respiratory distress secondary to cholestasis. Our goal for this R21 is to elucidate how the cholestasis in Abcb11 deficient mothers produces lethal neonatal respiratory distress. To accomplish this we propose two hypothesis driven Specific Aims:
Specific Aim 1 : We will test the hypothesis that offspring of Abcb11-null mothers have impaired lung maturation. Our preliminary data use an in vivo genetic model of maternal cholestasis.
Specific Aim 2 : We will test the hypothesis that maternal absence of Abcb11 exposes the developing fetus to an environment that alters expression of genes important for lung development. Our preliminary data indicate that the expression of surfactant B is reduced in the lungs of neonates from Abcb11- deficient mothers. We will determine mechanistically how lung maturation and function is impaired in neonates borne to Abcb11 deficient mothers. Successful completion of these exploratory studies will increase our knowledge of how maternal cholestasis disrupts prenatal lung development and facilitate preparation for an R01. The ultimate extension of the knowledge we acquire from these studies has the potential to reduce the untoward consequences of respiratory distress and the extent of respiratory damage in developing offspring after prenatal exposure to maternal cholestasis.

Public Health Relevance

Public Health Relevance: Maternal cholestasis frequently causes neonatal respiratory complications and is associated with sudden infant death syndrome. By identifying a gene causing maternal cholestasis, our studies will enhance infant health by ultimately facilitating development of a genetic test to screen mothers for defects in this gene. Equally important, these exploratory studies will provide insight into how fetal bile acid exposure disrupts lung maturation and function. These findings may lead to novel therapeutic approaches to ameliorate the impact of maternal cholestasis on fetal lung development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL114066-01
Application #
8283269
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Blaisdell, Carol J
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$218,750
Indirect Cost
$93,750
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Zhang, Yuanyuan; Li, Fei; Wang, Yao et al. (2015) Maternal bile acid transporter deficiency promotes neonatal demise. Nat Commun 6:8186
Zhang, Yuanyuan; Li, Fei; Patterson, Andrew D et al. (2012) Abcb11 deficiency induces cholestasis coupled to impaired ?-fatty acid oxidation in mice. J Biol Chem 287:24784-94
Nagai, Shinjiro; Takenaka, Kazumasa; Nachagari, Deepa et al. (2011) Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. Cancer Res 71:1781-91