# Project 2 - Cheng

> **NIH NIH P20** · WOMEN AND INFANTS HOSPITAL-RHODE ISLAND · 2021 · $328,813

## Abstract

SUMMARY / ABSTRACT
 Placental maldevelopment and dysfunction characterize pregnancies complicated by conditions such as
preeclampsia (PE). PE is a leading cause of maternal, fetal and neonatal mortality and morbidity and entails a
heterogeneous etiology. Women who developed PE are at increased risk for long-term cardiovascular and
metabolic disorders in later life. The lack of reliable methods for early diagnosis prior to clinical onset limits the
opportunities for prevention and timely treatment of PE. We recently demonstrated excessive presence of
aggregated proteins in the PE placenta. Our published work focused on transthyretin (TTR), the transporter of
thyroxine and retinol. Most importantly, we showed that PE serum containing aggregated TTR when
administered to pregnant mice could induce PE-like features. We detected elevated presence of aggregated
TTR in the sera from women with PE. A novel method using ProteoStat, a rotor dye that only binds to
aggregated proteins, has been developed. Our preliminary studies demonstrate that PE placenta displays
heavy staining for both aggregated TTR and amyloid precursor protein (APP), suggesting mechanistic
similarities to diseases such as Alzheimer's. Moreover, our preliminary data reveal that triggers that cause
endoplasmic reticulum (ER) stress induce TTR and APP aggregation through impaired unfolded protein
response (UPR) and autophagy-lysosome degradation machinery in human trophoblast cells. Here we
propose to test the central hypothesis that persistent environmental stress leads to chronic
endoplasmic reticulum (ER) stress, which exhausts the capacity of UPR and autophagy-lysosomal
degradation machineries, resulting in the accumulation of misfolded and aggregated proteins.
Aggregated proteins such as TTR and APP cause poor placentation and PE pathology. We further
hypothesize that PE is a risk factor for the onset of AD like symptoms. We propose the following specific
aims: 1) Using large sample size, adapt the protein aggregate detection assay as a predictive tool during early
pregnancy, 2) Characterize the molecular events that contribute to the accumulation of protein aggregates in
the cellular model of ER stress, and 3) Determine the generalizability of PE serum samples or aggregated
proteins to cause PE-like features in our humanized mouse model. Evaluate mice with induced PE for the
onset of AD-like features at 6-8 months age. The concept of protein aggregation in PE is novel and will provide
a platform for comprehensive studies to pursue investigation into the multifactorial etiology of the disorder and
the concepts for pathologies observed not only during pregnancy but also in later life.

## Key facts

- **NIH application ID:** 10145035
- **Project number:** 5P20GM121298-05
- **Recipient organization:** WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
- **Principal Investigator:** Shibin Cheng
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $328,813
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145035

## Citation

> US National Institutes of Health, RePORTER application 10145035, Project 2 - Cheng (5P20GM121298-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145035. Licensed CC0.

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