# Coupling between circadian rhythms and redox signaling in stem cell differentiation and adult neurogenesis

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $69,554

## Abstract

Project Summary
Circadian rhythms are necessary to coordinate the timing of key behavioral and physiological processes in
mammals [1-3]. However, while our understanding of the function of circadian clock genes in embryonic
development is rapidly advancing [4-6], the molecular mechanisms through which these rhythms emerge
during stem cell differentiation remain elusive [7]. Recently, signaling by reactive oxygen species (redox
signaling) has emerged as an essential link between cellular metabolism and circadian rhythms in adult
function [8, 9]. Signaling from the pentose phosphate pathway through production of redox cofactor NADPH is
an important regulator of transcriptional oscillations, influencing the expression of core circadian clock genes
through the redox-sensitive transcription factor NRF2 [10]. NRF2 is a crucial regulator of embryonic stem cell
pluripotency and self-renewal, but whether redox signaling contributes to the development of circadian rhythms
in differentiating stem cells remains completely unexplored [11].
Using fluorescent reporters of the hydrogen peroxide and Per2 expression, we propose to simultaneously
visualize reactive oxygen species and circadian rhythms in single cells for the first time. By combining this
novel model system with CRISPR/Cas9-mediated genome editing approaches, we will causally test the role of
redox signaling in the development of circadian rhythms in human induced pluripotent stem cells undergoing
directed differentiation to glutamatergic neurons. Using adult hippocampal neurogenesis as an in vivo model
system for neuronal differentiation, we will further explore the function of redox-circadian coupling in
coordinating the sequential development and circuit integration of adult-born granule cells.
The long-term objective of this proposal is to create a novel model system to explore the mechanisms through
which reciprocal interaction between redox and circadian transcription factor networks direct the proper
sequential timing of development. While the current proposal seeks to investigate how redox-circadian
coupling drives the differentiation of pluripotent and adult stem cells, we aim to describe a general paradigm for
the coordination of metabolism, cell division, and stem cell homeostasis in health and disease.
Hypothesis: We hypothesize that redox signaling drives the development of circadian rhythms in stem cells
following the loss of pluripotency, and that reciprocal regulation between redox signaling and circadian rhythms
drives the cellular maturation. We predict that disrupting redox-circadian coupling in adult neural stem cells
through acute Nrf2 knockout will induce cell division and differentiation, but hinder the development of
circadian rhythms and normal maturation of adult-born granule cells. We will test this hypothesis in the
following aims:
Aim 1: Causally link redox signaling to circadian rhythm development in human induced pluripotent stem cells
Aim 2: Determine impact of Nrf2 K...

## Key facts

- **NIH application ID:** 10155930
- **Project number:** 1F32MH125600-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel Maxim Iascone
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,554
- **Award type:** 1
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155930

## Citation

> US National Institutes of Health, RePORTER application 10155930, Coupling between circadian rhythms and redox signaling in stem cell differentiation and adult neurogenesis (1F32MH125600-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10155930. Licensed CC0.

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