# Decidual nutrient sensing and IGFBP-1 phosphorylation in placental insufficiency

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $271,276

## Abstract

Intrauterine growth restriction (IUGR) increases the risk for perinatal complications and predisposes for adult
disease. However, the pathophysiology underlying IUGR remains poorly understood, no specific treatment is
available and biomarkers for early detection are lacking. Maternal circulating IGF1 regulates fetal growth by
affecting placental function and low maternal IGF1 is associated with IUGR. The bioavailability of maternal
IGF1 is strongly influenced by a family of IGF binding proteins (IGFBPs), in particular IGFBP1, which binds
IGF1 and decreases its bioavailability. In addition, phosphorylation of IGFBP1 markedly increases its binding
affinity for IGF1, thereby limiting IGF1 bioactivity further. The decidua is the primary source of maternal
IGFBP1 during pregnancy. The role of hyperphosphorylation of maternal IGFBP1 in the development of IUGR
is unknown and our understanding of the molecular mechanisms regulating decidual IGFBP1 secretion and
phosphorylation is limited. Herein, we will address this gap of knowledge by testing the central hypothesis that
inhibition of decidual mechanistic target of rapamycin (MTOR) signaling and activation of the amino acid
response (AAR) in placental insufficiency increases the secretion of IGFBP1 and its phosphorylation on
specific serine residues and that increased phosphorylation of IGFBP1 in the maternal circulation in early
pregnancy is strongly associated with the development of IUGR. This hypothesis is supported by compelling
preliminary data including the demonstration that i) decidual MTOR signaling is inhibited and IGFBP1 content
and phosphorylation are increased in IUGR, (ii) MTOR inhibition is mechanistically linked to increased
secretion and phosphorylation of IGFBP1 in decidualized human endometrial stromal cells and (iii)
hyperphosphorylation of IGFBP1 in the maternal circulation in early pregnancy is associated with the
development of IUGR. We propose three aims. In Aim 1 we will determine the relationship between maternal
serum IGFBP1 phosphorylation in early pregnancy and IUGR. In Aim 2 we will determine decidual MTOR,
CSNK2 and AAR activity and IGFBP1 levels and phosphorylation in decidua and maternal serum in IUGR in
late pregnancy. In Aim 3 we propose to establish the mechanistic role of MTOR and AAR signaling in
regulating decidual IGFBP1 secretion and phosphorylation using gene silencing and pharmacological
approaches in human endometrial stromal cell lines and in primary human decidual stromal cells. We
anticipate that the proposed work will identify a novel key mechanism underlying the development of human
IUGR and establish hyperphosphorylation of maternal IGFBP1 as an early biomarker of IUGR. This work will
have a sustained and significant impact on the research area because it will increase our understanding of
IUGR, generate new tools for early detection and pave the way for targeting decidual IGFBP1
secretion/phosphorylation as a new intervention strategy in IUGR.

## Key facts

- **NIH application ID:** 9965999
- **Project number:** 5R01HD089980-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Madhulika Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $271,276
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965999

## Citation

> US National Institutes of Health, RePORTER application 9965999, Decidual nutrient sensing and IGFBP-1 phosphorylation in placental insufficiency (5R01HD089980-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9965999. Licensed CC0.

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