# Defining the link between trisomy 21 and placentation defects

> **NIH NIH F32** · UNIVERSITY OF COLORADO · 2024 · $76,408

## Abstract

Down’s Syndrome (T21) is the most common aneuploidy disorder in humans. T21 pregnancies are at an
increased risk of adverse pregnancy outcomes including stillbirth and intrauterine growth restriction resulting
from placental insufficiency. T21 is also accompanied by comorbidities including congenital heart disease, also
linked to inadequate placentation. Coincidentally, T21 placental syncytiotrophoblasts that act as the primary
barriers at the maternal-fetal interface fail to adequately fuse into multinucleated syncytial plaques, and the
underlying etiology is unknown. We hypothesize that defects in T21 syncytiotrophoblast differentiation occur
during peri-implantation development and contribute to a wide range of diseases in individuals with T21. The
long-term goals of our research are to provide a mechanism by which syncytiotrophoblast differentiation is
disrupted in T21 and provide opportunities for therapeutic intervention. In Aim 1, we will identify transcriptional
differences of T21 implantation-stage trophoblasts by differentiating six pairs of T21 and matching euploid
induced pluripotent stem (iPS) cell lines into syncytiotrophoblast-like cells with treatment of BMP4, A83-01, and
PD173074 (BAP) and performing RNA-sequencing. In Aim 2, we will assess canonical estrogen-driven
transcription in T21 and euploid BAP-treated iPS cells. We will knockdown the third copy of NRIP1, an estrogen
receptor inhibitor on chromosome 21, with CRISPR/Cas9 technology in T21 BAP-treated iPS cells to determine
the influence of estrogen receptor inhibition on T21 syncytiotrophoblast fusion. We will also overexpress a third
copy of NRIP1 in euploid lines and measure estrogen mediated transcriptional activity and syncytiotrophoblast
cell fusion. These results will help to confirm or deny the involvement of NRIP1 and canonical estrogen signaling
in the T21 syncytiotrophoblast disease phenotype. In Aim 3, we will differentiate T21 and euploid iPSCs to
cardiomyocytes and supplement them with conditioned medium from T21 and euploid trophoblast cultures to
reveal a relationship between impaired T21 trophoblasts on cardiomyocyte development. In summary, our
proposal uses cutting edge models and techniques that have not been used in T21 trophoblast research to
demonstrate the significance of abnormal placentation on long-term health.

## Key facts

- **NIH application ID:** 10999075
- **Project number:** 1F32HD116568-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Deirdre Logsdon
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,408
- **Award type:** 1
- **Project period:** 2024-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999075

## Citation

> US National Institutes of Health, RePORTER application 10999075, Defining the link between trisomy 21 and placentation defects (1F32HD116568-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/10999075. Licensed CC0.

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