# Novel Approaches to Understanding the Nutrient Regulation of Fetal Somatic Growth

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2021 · $440,885

## Abstract

Liver growth and differentiation are processes critical to metabolic adaptation of the newborn. Perturbation of
these processes contributes to neonatal disorders and to the fetal origins of adult metabolic disease. The
biology of fetal liver development also has implications for cell-based therapy for liver disease, hepatic
carcinogenesis and the regulation of fetal somatic growth. This application is for continuation of a project that
has focused on late gestation liver development in the rodent. The project has been based on the central
hypothesis that fetal liver development in late gestation is regulated by mechanisms distinct from those that
control liver function and mass in the adult. During the past cycle, our work focused on signaling by the
mechanistic Target of Rapamycin (mTOR), a nutrient-sensing Ser/Thr kinase. We found that fetal rat
hepatocytes are resistant to the anti-proliferative actions of the mTOR inhibitor, rapamycin. This observation
led us to refocus our efforts on the identification of novel mechanisms for nutrient-responsive gene regulation,
metabolic control and cell signaling in the fetus. We plan to identify such mechanisms by focusing on two
comparisons, the late gestation fetal rat versus postnatal animals, 1 day to 35 days of age, and the normal late
gestation fetus versus the intrauterine growth restricted fetus. We will study immunopurified fetal and postnatal
hepatocytes using standard biochemical and cell biology methods and -omic approaches to achieve a long
term goal of better understanding the nutrient regulation of fetal somatic growth. We propose the following
specific aims. In Specific Aim 1, we will identify nutrient-responsive mechanisms that regulate fetal and
perinatal hepatic gene expression. We will test the hypothesis that late gestation fetal-to-postnatal differences
in hepatic gene expression involve the modification of histones and resulting changes in chromatin structure,
and that this mode of transcriptional control mediates effects of nutrient restriction induced by maternal fasting
late in gestation (E18 to E20). In Specific Aim 2, we will characterize the mechanisms that regulate nutrient-
responsive mRNA translation in late gestation and newborn hepatocytes. Based on our studies showing
differences in regulation of protein synthesis in fetal versus adult liver, we will focus on the hypothesis that
differential expression of protoeforms of the eukaryotic translation initiation factor eIF4G1 is critical to nutrient-
mediated fetal translation control. In Specific Aim 3, we will study the regulation of mitochondrial biogenesis
and metabolism during the perinatal transition and in normal and growth restricted fetal rats. We will test the
hypothesis that nutrient restriction late in gestation induces fetal hepatic mitochondrial biogenesis, a reduction
in fermentative glycolysis and an increase in oxidative phosphorylation. Our preliminary studies and published
data link mitochondrial biogenesis...

## Key facts

- **NIH application ID:** 10167744
- **Project number:** 5R01HD024455-31
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Philip A. Gruppuso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,885
- **Award type:** 5
- **Project period:** 1989-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167744

## Citation

> US National Institutes of Health, RePORTER application 10167744, Novel Approaches to Understanding the Nutrient Regulation of Fetal Somatic Growth (5R01HD024455-31). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167744. Licensed CC0.

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