# Genomic Dissection of Placental Lesions in Preeclampsia

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $426,639

## Abstract

PROJECT SUMMARY
Preeclampsia (PE) affects 3-8% of pregnancies and is a leading cause of severe maternal morbidity and
mortality. PE pathogenesis involves abnormal EVT differentiation and invasion, which leads to failed remodeling
of spiral arteries, resulting in hypoperfusion of the placenta that causes oxidative stress. Developmental
abnormalities in the placenta manifest as histopathological lesions that arise from these defects and include
maternal vascular malperfusion (MVM), a constellation of gross and microscopic findings that represent
abnormal perfusion through the maternal vascular channels. Recently, widespread placental mosaicism and
frequent mutations have been characterized in normal placental tissue, suggesting that this is a common feature
of placental development arising from distinct clonal expansions. The role that these mutations play in
histopathological lesions such as MVM, placental dysfunction, maternal-fetal immune tolerance is poorly
understood. We hypothesize that somatic mutations contribute to the etiology of preeclampsia by
affecting trophoblast differentiation, proliferation and immunogenicity. We will model the functional
consequences of somatic mutations on in vitro trophoblast proliferation and differentiation by establishing
trophoblast stem cell (TSC) lines from human placenta-derived induced pluripotent stem cells (iPSC) and use
CRISPR-Cas9 to knock-in previously identified PE-associated loss-of-function mutations in each iPSC line. We
will characterize the trophoblast proliferation and differentiation potential and immunogenicity of mutated and
isogenic control iPSC-TSC lines using qRT-PCR, flow cytometry, immunocytochemistry, functional assays, and
cytokine arrays at the TSC (cytotrophoblast/CTB) stage and following differentiation into syncytiotrophoblasts
(STB) and extravillous trophoblasts (EVT). Next, we will characterize the mutational landscape of histopathologic
lesions (MVM) in placentas from severe early onset PE and without PE. We will perform whole genome
sequencing at 30X coverage and single nucleotide, copy number and structural variant calling to identify germline
(maternal and fetal) and somatic mutations within the placenta and placental lesions. We will calculate
mutational burden, predict immunogenicity and perform a clinical enrichment analysis to identify mutations
enriched in placental lesions relative to matched normal regions and in preeclampsia relative to normal, which
will identify mutations associated with PE and MVM as candidates for further functional testing. Modeling the
functional roles of placental mutations with in vitro modeling of trophoblast differentiation, proliferation and
immunogenicity will further our understanding of the cellular dynamics of placental dysfunction in preeclampsia.

## Key facts

- **NIH application ID:** 10742701
- **Project number:** 1R21HD110893-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Kathleen Marie Fisch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $426,639
- **Award type:** 1
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10742701

## Citation

> US National Institutes of Health, RePORTER application 10742701, Genomic Dissection of Placental Lesions in Preeclampsia (1R21HD110893-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10742701. Licensed CC0.

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