# Rubicon: a novel target of sex-specific placental dysfunction in maternal obesity

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $192,500

## Abstract

PROJECT SUMMARY
More than 65% of women entering pregnancy in the US are overweight or obese. Obesity in pregnancy
predisposes the offspring to obesity, and cardiovascular and metabolic disorders, thus initiating a “vicious
cycle” of obesity and its health-related consequences in subsequent generations even in the absence of further
intrauterine stressors. The worldwide epidemic of obesity and cardiovascular and metabolic diseases,
therefore, is not only a result of the sedentary lifestyle or poor diet; it is also a consequence of a
“developmental program” switched on as a result of an adverse in utero environment. The absence of
therapeutic strategies to prevent developmental programming is a consequence of our lack of knowledge of
the mechanisms whereby maternal obesity affects the health of future generations. The placenta is a crucial
determinant of healthy fetal growth and development, but the consequences of obesity for placental health are
only now beginning revealed. Data from our laboratory have shown an accumulation of inflammatory cytokine
TNFα in the placentas of female fetuses is associated with an activation of pro-inflammatory transcription
factor nuclear factor κappa B (NFκB). Inflammation is tightly regulated by autophagy, a cellular recycling
process, and unresolved inflammation has been associated with a disruption of autophagy, which, in turn,
leads to cardiovascular and metabolic diseases. Our recent data suggest that placentas of both male and
female offspring from obese women show inhibition of autophagy. However, there are significant sex
differences in the mechanisms. In the placentas of males, inhibition of autophagy is associated with a decrease
in critical autophagy coordinating transcription factor EB. In the placentas of females, in contrast, inhibition of
autophagy is linked to inflammation via Rubicon (RUN domain and cysteine-rich domain containing Beclin1-
interacting protein), a newly identified negative regulator of autophagy. We found an increase in Rubicon
expression and Beclin 1 binding in the placentas of females of obese women with this phenomenon not seen in
placentas of males. Our data suggest that these processes are, at least in part, regulated by TNFα-induced
inflammation. Here we hypothesize that in response to inflammation generated in utero by maternal obesity, an
increase in placental Rubicon expression occurs causing changes in its protein-protein interaction and thereby
inhibiting placental autophagy. We will address this hypothesis with three specific aims: 1). Identify the
mechanisms that regulate expression of Rubicon and its binding to Beclin1 in the human placenta with
maternal obesity. 2). Determine the molecular basis relating Rubicon to the inhibition of autophagy in the
placenta with obesity. 3). Identify sex-dependent mechanisms that regulate Rubicon signaling in the placenta
with maternal obesity. This study will provide mechanistic insights that will systematically and rigorously fill
...

## Key facts

- **NIH application ID:** 10000193
- **Project number:** 5R21HD097398-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alina Maloyan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-08-22 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000193

## Citation

> US National Institutes of Health, RePORTER application 10000193, Rubicon: a novel target of sex-specific placental dysfunction in maternal obesity (5R21HD097398-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000193. Licensed CC0.

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