# Oocyte genomic instability as a driver of the aging ovarian innate immune response

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $465,952

## Abstract

PROJECT SUMMARY
Overall tissue function deteriorates with age, but the female reproductive system is the first to age. Female
reproductive aging is characterized by a decline in egg quantity and quality which contributes to miscarriages,
infertility, and birth defects. Cessation of reproductive function at menopause also accelerates overall aging
because the gonadal hormone, estrogen, regulates numerous tissues (e.g., brain, heart, bone, immune cells,
reproductive tract). The consequences of female reproductive aging are significant because women are delaying
childbearing, and medical interventions have increased the gap between menopause and lifespan. Thus there
is a critical need to discover the molecular mechanisms underpinning female reproductive aging. A hallmark of
aging tissues is “inflammaging” or chronic physiologic stimulation of the innate immune system leading to low
levels of sterile inflammation with age. The Duncan and Gerton laboratories recently discovered a prominent
inflammatory signature in the aging ovary, both within the somatic compartment of the follicle (granulosa cells)
and in the stroma or tissue microenvironment. However, the mechanism by which this age-related ovarian
inflammation is generated, sustained, and propagated across cell types is not known and must be addressed to
advance the field. Our long-term goal is to discover the molecular regulators of female reproductive aging from
perspectives of the gamete, follicle, and ovarian microenvironment. Thus, our application is aligned with the
NICHD’s Fertility and Infertility Branch high-priority research area of reproductive transitions. The major objective
of this grant is to discover signals exchanged between oocytes and their surrounding granulosa cells, and how
intercellular communication drives the broader spatiotemporal pattern of ovarian aging. Our overarching
hypothesis is that, with advanced reproductive age, cytosolic DNA originating from loss of genomic stability in
the oocyte stimulates the innate immune response and inflammatory pathways in ovarian granulosa cells which
are then further amplified by the tissue microenvironment. Central to our model is the cGAS-STING pathway
which links genomic instability and inflammatory responses across cells within a tissue. This pathway has never
been examined in the ovary, nor within the context of ovarian aging, but our preliminary data strongly support a
fundamental role. To address our overarching hypothesis, we will identify age-associated genomic instability
signatures in the mouse oocyte that serve as trigger signals (Aim 1). We will then determine how granulosa cells
integrate oocyte-derived signals to initiate an age-associated innate immune response (Aim 2). Finally, we will
discover how the spatio-temporal architecture of ovarian fibrosis and inflammaging govern the follicular response
and vice versa through spatial transcriptomics (Aim 3). These aims will provide a comprehensive and integrated
molecular m...

## Key facts

- **NIH application ID:** 10470296
- **Project number:** 5R01HD105752-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Francesca E. Duncan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $465,952
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470296

## Citation

> US National Institutes of Health, RePORTER application 10470296, Oocyte genomic instability as a driver of the aging ovarian innate immune response (5R01HD105752-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470296. Licensed CC0.

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