# Oogenic JNK in gonadotoxic chemotherapy-induced primary ovarian insufficiency

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $627,728

## Abstract

PROJECT SUMMARY
The advances in cancer survival rates greatly enhance the awareness of side effects of cancer therapy and long-
term life quality after cancer. Primary ovarian insufficiency (POI) and infertility are major side effects in young
female cancer patients. As the female gonad, the ovary contains various stages of follicles as its functional unit.
Each follicle consists of a central germ cell oocyte and surrounding somatic cells. Primordial follicles are at the
earliest stage and remain quiescent for months or decades to establish ovarian reserve, a marker of female
reproductive life span. Our research teams have demonstrated that commonly used chemotherapeutic drugs,
including doxorubicin (DOX), cisplatin (CDDP), and cyclophosphamide (CPA), primarily induce DNA damage
and apoptosis of the oocytes in primordial follicles, resulting in the entire primordial follicle death, POI, infertility,
and endocrine disorders. Mechanistically, the gonadotoxic anti-cancer agents activate DNA damage response
(DDR)-TAp63-related signaling to trigger oocyte apoptosis. However, the underlying mechanism remains
largely unknown. Using wild type (WT) mice and a genetically modified mouse model with oocyte-specific
deletion of all three c-Jun NH2-terminal kinase (JNK) genes (Jnk1/2/3), our preliminary studies demonstrated
that: (1) JNK was selectively activated in primordial follicle oocytes following DOX treatment; (2) a selective JNK
inhibitor, SP600125, blocked DOX-induced activation of TAp63 and follicle atresia; (3) oogenic deletion of JNK
didn’t affect normal ovarian functions but prevented the induction of apoptotic genes and primordial follicle atresia
following DOX treatment; and (4) pharmacological inhibition or genetic deletion of JNK blocked TAp63
activation induced by CDDP and CPA, the other two gonadotoxic anti-cancer agents. Based on these preliminary
data and the fact that JNK has been found to pro-oncogenic in certain types of cancer such as leukemia, our
central hypothesis is that JNK critically regulates DDR-TAp63-related apoptotic signaling in primordial
follicle oocytes following treatment with gonadotoxic anti-cancer agents; and pharmacological inhibition
of JNK prevents chemotherapy-induced POI and infertility without compromising anti-cancer efficacy of
chemotherapy. We will use DOX as a representative gonadotoxic anti-cancer agent to test our hypothesis. In
Aim 1, we will investigate the mechanism by which JNK regulates DDR-related apoptotic signaling in primordial
follicle oocyte following DOX treatment. In Aim 2, we will determine the efficacy of pharmacological inhibition of
JNK against DOX treatment on protecting ovarian reserve in a young leukemic female mouse model. Completion
of these two Specific Aims will allow us to (1) elucidate the molecular mechanisms of oogenic JNK in contributing
to DDR-TAp63-related apoptotic signaling in primordial follicle oocytes following treatment with gonadotoxic
chemotherapeutic agents, and...

## Key facts

- **NIH application ID:** 10945577
- **Project number:** 1R01HD115810-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** So-Youn Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,728
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945577

## Citation

> US National Institutes of Health, RePORTER application 10945577, Oogenic JNK in gonadotoxic chemotherapy-induced primary ovarian insufficiency (1R01HD115810-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10945577. Licensed CC0.

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