# Regulatory Landscape of the Aging Human Ovary

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $332,478

## Abstract

Reproductive aging is a major health, personal and societal issue, but ovarian aging has received limited
scientific attention, even in large genomic survey projects. Ovarian aging influences diverse health outcomes in
women including lifespan, cardiovascular disease, metabolic syndromes, neurodegenerative disorders and
various types of cancer. Yet the molecular mechanisms underlying ovarian aging, timing of menopause and
inter-organ feedback loops remain elusive. As one of the most dynamic organs in the human body, the ovary
undergoes significant remodeling across the entire reproductive period. The dynamic transcriptional regulation
of and interactions between oocytes and their surrounding cells during aging remain unknown. The objective of
this proposal is to understand the regulatory landscapes underlying the complex interplay among the different
cell types in the ovary and to investigate the molecular mechanisms that regulate the remarkably complex
processes of reproductive aging. We will apply powerful single-cell (sc) RNA-seq and scATAC-seq analysis to
define specific transcriptional programs and regulated enhancer networks that are altered in distinct ovarian cell
types or subtypes during aging. By defining the roles of specific enhancers in specific cell types, and how these
change with aging, we aim to understand the identities of the regulatory factors and environmental signals that
impact aging in each ovarian cell type. Genetic variation affecting enhancer selection and function is a major
determinant of differences in cell-specific gene expression between individuals. To investigate the mechanisms
by which altered regulatory enhancer landscapes contribute to ovarian aging by licensing changes in
transcriptional programs, we will investigate the roles of genetic variants associated with age at menopause,
detected by genome-wide association studies (GWAS), in modulating transcription programs during ovarian
aging. In particular, we hope to provide mechanistic insights into genetic modulation of transcriptional regulation
of critical homeostatic and inflammatory pathological functions in the granulosa cells (GC), the supporting cell
type immediately surrounding the oocyte, by modeling the causal regulatory variants in human GC models that
are differentiated from human ESCs engineered to carry causal variants by CRISPR gene editing.

## Key facts

- **NIH application ID:** 10264170
- **Project number:** 5R01AG069750-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL G ROSENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,478
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264170

## Citation

> US National Institutes of Health, RePORTER application 10264170, Regulatory Landscape of the Aging Human Ovary (5R01AG069750-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10264170. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*