# ONTOGENY OF HEPATIC ION TRANSPORT

> **NIH NIH R01** · YALE UNIVERSITY · 1994 · $300,181

## Abstract

The overall objective of the present proposal is to define further the
cellular and molecular mechanisms underlying the ontogenic expression of
hepatic bile acid transport.  It is our hypothesis that the developmental
regulation of these proteins which mediate uptake and secretion of bile
acids occurs predominantly at the level of transcription in response to
ontogenic programming, the hormonal milieu, and an increasing substrate
[ bile acid ] pool.  The following specific aims are designed to test
this hypothesis as well as to determine if alternative or complementary
mechanisms (translational and post-translational) are involved in the
process.  The specific aims are to determine:  (1) the factors involved
in the developmental expression of the basolateral Na+-dependent and the
canalicular potential-driven bile acid transporters; (2) the number of
canalicular bile acid transporters, their driving forces [potential vs.
ATP dependent] and their expression during perinatal development; and (3)
the molecular mechanisms underlying the ontogenic and tissue-specific
expression of the basolateral and canalicular bile acid transporters.
An integrated experimental approach will employ membrane vesicle
transport assays, immunochemical quantitation and immunocytochemical
localization of the transport proteins, and Northern blot analysis of
transporter mRNA levels.  These studies will determine whether the
canalicular ATP-dependent bile acid transporter is functional in neonatal
liver and whether its activity can be distinguished from the potential-
driven system through its pattern of expression and through selective
reconstitution of transport activity into synthetic proteoliposomes.  The
cloning of the basolateral Na+-dependent and the canalicular potential-
driven bile acid transporter genes including their promoters will allow
the identification of regulatory elements involved in the ontogenesis of
transport activity and mediating the effects of hormones and bile acids
on gene transcription.  The cis-acting elements and trans-acting factors
that direct the liver-specific and ontogenic expression of these
transporters will be defined through an analysis of DNA and nuclear
protein interactions.  The cis-regulatory regions of these genes will be
characterized further by linking various portions of the promoter regions
to a firefly luciferase reporter for transfection assays in cultured
primary rat hepatocytes.  The ability of bile acids to regulate the
promoter activities of the transporters will be investigated in
experiments utilizing in vitro transfection assays.  Transgenic mice will
be used to assess DNA regulatory regions required to direct the correct
acinar, developmental, and tissue-specific pattern for expression of the
Na+-dependent bile acid transporter.  These studies will provide further
insights into the factors contributing to the physiologic immaturity of
hepatic excretory function and susceptibility to cholestatic liver
disease in the ne...

## Key facts

- **NIH application ID:** 2198057
- **Project number:** 5R01HD020632-09
- **Recipient organization:** YALE UNIVERSITY
- **SAM.gov UEI:** FL6GV84CKN57
- **Principal Investigator:** FREDERICK J SUCHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $300,181
- **Award type:** 5
- **Project period:** 1985-09-01 → 1998-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2198057

## Citation

> US National Institutes of Health, RePORTER application 2198057, ONTOGENY OF HEPATIC ION TRANSPORT (5R01HD020632-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2198057. Licensed CC0.

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