# Embryonic stem cell self-renewal

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $330,000

## Abstract

Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of the pre-implantation
blastocyst. ESCs provide a powerful platform for elucidating gene function and creating disease models. So far,
the application of ESC-based technologies has been limited to mice and rats, because germline competent
ESCs have not yet been established from non-rodent species. Our previous work established that efficient self-
renewal of mouse and rat ESCs could be achieved by dual inhibition of glycogen synthase kinase 3 (GSK3)
and mitogen-activated protein kinase kinase (MEK). GSK3 has two paralogous members, GSK3α and GSKβ,
which share nearly identical kinase domains. Similarly, extracellular signal-regulated kinase (ERK), the only
known physiological substrates of MEK, also has two highly homologous paralogs, ERK1 and ERK2. Despite
their high levels of homology, GSK3α and GSK3β possess distinct functions in regulating ESC self-renewal;
the same is the case for ERK1 and ERK2. Therefore, fine-tuning of GSK3 and ERK signaling becomes critical
in achieving optimal ESC self-renewal. By taking advantage of the chemical-genetic approach and the ESC
platform, we propose to investigate the molecular mechanisms underlying the distinct functions of individual
GSK3 and ERK paralogs in ESC self-renewal. In Aim 1, we will identify and characterize GSK3 paralog-
specific substrates and downstream targets. We will also determine the amino acid variances responsible for
the distinct functions of GSK3α and GSK3β. In Aim 2, we will identify and characterize ERK paralog-specific
substrates in the cytoplasm and nucleus and investigate how subcellular localization of ERK1 and ERK2
affects their functions in ESCs. In Aim 3, we will fine-tune GSK3 and ERK signaling in mouse and human naïve
ESCs to achieve optimal self-renewal effect. Success with these three aims will not only provide insights into
the molecular basis of ESC self-renewal, but will also have far-reaching implications for our deep
understanding of pathological conditions caused by dysfunction of GSK3 and ERK.

## Key facts

- **NIH application ID:** 10135692
- **Project number:** 5R01GM129305-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Qilong Ying
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135692

## Citation

> US National Institutes of Health, RePORTER application 10135692, Embryonic stem cell self-renewal (5R01GM129305-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135692. Licensed CC0.

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