# Development of approaches for inducible trophoblast-specific gene modulation: the role of trophoblast Lat1 in the regulation of placental function and fetal growth

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $635,433

## Abstract

PROJECT
SUMMARY
The
placental
 precise mechanisms causing abnormal fetal growth remain to be fully established, however changes in
 amino acid transport may contribute to both IUGR and fetal overgrowth. The Large Neutral Amino
Acid Transporter Small Subunit 1 (LAT1) mediates transplacental transfer of essential amino acids and thyroid
hormones by the transporter System L. Importantly, placental System L amino acid transporter activity is
decreased in human IUGR and increased in fetal overgrowth in women. However, it remains unknown if
changes in the expression/activity of placental LAT1 are mechanistically linked to placental function, fetal
growth and offspring cardiometabolic outcomes. Importantly, global Lat1 deletion leads to embryonic lethality in
mid-gestation in mice, making it difficult to determine the role of LAT1 for placental function. Other genes,
albeit not embryonically lethal, may influence both early placental development and the function of the
established placenta, requiring tools to `turn-off' or `turn-on' genes at specific time points of gestation. Thus,
there is an urgent need to develop approaches to achieve inducible, trophoblast-specific gene modulation. The
objective of this proposal is to develop and validate novel approaches for inducible trophoblast-specific gene
modulation in mice and to test the central hypothesis that restoring normal trophoblast Lat1 expression rescues
the embryonic lethality of global Lat1 deletion and that trophoblast-specific Lat1 knockdown after the
establishment of the placenta decreases placental transport of essential amino acids and inhibits placental
mTOR, mitochondrial respiration and protein synthesis, restricts fetal growth and programs offspring
metabolism and cardiovascular function. We propose three Specific Aims: Aim 1: Develop and validate mice
with inducible trophoblast-specific Lat1 gene modulation. Our approach will be to generate mice with
doxycycline-inducible, trophoblast-specific Lat1 gene knockdown or rescue in Lat1-/- embryos using piggyBac
transposase-enhanced transgenesis, lentivirus-mediated transduction of blastocysts and tetraploid
complementation assay, respectively. Aim 2: Determine the effect of trophoblast-specific Lat1 modulation
on placental function, fetal growth and offspring long-term outcomes. Our approach will be to (1) induce
Lat1 knockdown after the establishment of the placenta and (2) rescue trophoblast Lat1 gene expression in
global Lat1 knockout (Lat1-/-) embryos. We will determine transplacental transport of amino acids and thyroid
hormones, placental mTOR signaling activity, mitochondrial respiration and protein synthesis, fetal growth and
offspring long-term metabolic and cardiovascular function Aim 3: Establish the effect of LAT1 modulation
on primary human trophoblast syncytialization and function. Our approach will be to isolate primary
human trophoblast (PHT) cells from term placentas and determine syncytialization, amino acid and thyroid
horm...

## Key facts

- **NIH application ID:** 10818620
- **Project number:** 5R01HD105701-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Thomas L Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,433
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818620

## Citation

> US National Institutes of Health, RePORTER application 10818620, Development of approaches for inducible trophoblast-specific gene modulation: the role of trophoblast Lat1 in the regulation of placental function and fetal growth (5R01HD105701-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10818620. Licensed CC0.

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