# MOLECULAR AND METABOLIC ASPECTS OF IMPLANTATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $419,820

## Abstract

PROJECT SUMMARY
Early pregnancy loss affects roughly 15% of known pregnancies and may be even more common in obese
women. A prominent cause of early pregnancy loss is failure of implantation, which requires that the uterine
endometrial stromal cells undergo decidualization. Additionally, recent work has revealed an important role for
metabolic regulation in in this process. Specifically, the decidualizing stromal cells produced less ATP and
more NADPH and ribose-5-phosphate via the pentose phosphate pathway, which is used to produce
nucleotides. Thus this event occurs at the expense of reduced glycolysis; how these cells compensate for this
decrease in energy production is unknown. This gap in knowledge limits our ability to discover new therapeutic
strategies to improve pregnancy outcomes.
Our long-term goal is to understand the metabolic and molecular mechanisms responsible for endometrial
stromal cell decidualization so that effective therapies for improving this process can be developed and used to
prevent early pregnancy loss, especially in the increasing population of obese women. Here, we will test
the central hypothesis that initiation of the cellular recycling pathway autophagy plays a key role in
decidualization in both humans and mice. We will test our hypothesis by pursuing the following specific aims:
Aim 1. Determine the role of autophagy in decidualization. Our working hypothesis is that decidualization
depends on induction of autophagy both in vitro and in vivo. We will determine the effect of genetic or
pharmacologic block of autophagy on decidualization of both mouse and human endometrial stromal cells. We
will assess the effect of autophagy inhibition on both artificial and pregnancy-induced decidualization in a
genetic knock out mouse model deficient in two different autophagic genes, Atg16L1 and Beclin1, allowing us
to assay not only decidualization, but also embryo implantation and pregnancy outcomes. Aim 2. Define the
function of GLUT8 in decidualization. We will test the hypothesis that the impaired decidualization and
subfertility of Glut8 knockout mice are due to a loss of autophagy in endometrial stromal cells. We will address
this by measuring autophagy in Glut8-null endometrial stromal cells and asking whether the defects can be
reversed by inducing autophagy. We will also determine whether inducing autophagy can improve pregnancy
rates in Glut8 knockout mice. Aim 3: Determine the mechanism by which saturated fatty acids impair
decidualization. We will test our hypothesis that saturated free fatty acids inhibit autophagy by examining
steps in autophagy and the signaling pathway that activates autophagy. We will also perform in vitro and in
vivo mouse and human experiments to assess the ability of activators of autophagy to reverse the deleterious
effects of high-fat diet, saturated fatty acids, and obesity on decidualization and reproductive outcomes. U[on
completion of these aims we expected the following outcomes: 1...

## Key facts

- **NIH application ID:** 9932460
- **Project number:** 5R01HD065435-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ramakrishna Kommagani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,820
- **Award type:** 5
- **Project period:** 2010-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932460

## Citation

> US National Institutes of Health, RePORTER application 9932460, MOLECULAR AND METABOLIC ASPECTS OF IMPLANTATION (5R01HD065435-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932460. Licensed CC0.

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