# Trophoblast mTOR: a critical hub linking maternal nutrient supply to placental function, fetal growth and fetal islet function

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $475,551

## Abstract

Both intrauterine growth restriction (IUGR) and fetal overgrowth increase the risk for perinatal complications
and predispose the individual for developing obesity, diabetes and cardiovascular disease in childhood and
adult age. Thus, a mechanistic understanding of the regulation of fetal growth is critical for identifying the
causes of major pregnancy complications and developmental programming of adult disease. Placental mTOR signaling is inhibited in IUGR and activated in pregnancies complicated by fetal overgrowth. Trophoblast mTOR signaling responds to an array of diverse maternal nutritional and metabolic signals. For example, trophoblast mTOR is activated by insulin/IGF-I, glucose and amino acids, fatty acids and folate, and inhibited by cortisol, adiponectin, infection and reduced uteroplacental blood flow. In addition, mTOR is a positive regulator of trophoblast amino acid and folate transport and mitochondrial respiration. Collectively, this data suggest that trophoblast mTOR signaling functions as a critical hub linking maternal nutrient supply to placental function, fetal growth and developmental programming. However, data demonstrating that changes in trophoblast mTOR signaling directly regulates placental function in vivo, causes abnormal fetal growth and programs adult disease is lacking, representing a major gap in knowledge and a roadblock for future targeting of trophoblast mTOR signaling to mitigate IUGR and fetal overgrowth. Our central hypothesis is that inhibition of trophoblast mTOR signaling is mechanistically linked to decreased placental nutrient transport and mitochondrial respiration, fetal growth restriction and impaired fetal pancreatic isletcell function. Our approach will be to use gene targeting in cultured primary human trophoblast (PHT) cells and a trophoblast specific inducible mTOR knockdown mouse that we have recently developed. In Aim 1 we will determine the mechanistic role of trophoblast mTOR signaling in the regulation of placental function and fetal growth. We hypothesize that (1) restoring normal mTOR signaling rescues the phenotype in PHT cells isolated from IUGR pregnancies and that (2) trophoblast-specific mTOR knockdown in mice decreases placental nutrient transport and mitochondrial respiration and inhibits fetal growth. In Aim 2, we will establish the mechanistic role of trophoblast mTOR signaling in regulating fetal islet function Our working hypothesis is that inhibition of trophoblast mTOR signaling inhibits fetal islet function mediated by exosomal miRNAs released into the fetal circulation. The proposed work is significant because it will generate novel mechanistic information leading to a better understanding of the underpinnings of abnormal fetal growth and in utero programming of metabolic disease, which will have a sustained and significant impact on the field. The proposed work is innovative because the trophoblast specific inducible mTOR knockout mouse, generated using piggyBac trans...

## Key facts

- **NIH application ID:** 10133103
- **Project number:** 5R01HD068370-08
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Thomas Jansson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $475,551
- **Award type:** 5
- **Project period:** 2011-07-25 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133103

## Citation

> US National Institutes of Health, RePORTER application 10133103, Trophoblast mTOR: a critical hub linking maternal nutrient supply to placental function, fetal growth and fetal islet function (5R01HD068370-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133103. Licensed CC0.

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