# Contribution of Nuclear S1P Signaling to Microtubule Targeting Agent-Induced Changes in Transcriptional Activity in Human iPS-SNs

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $61,979

## Abstract

PROJECT SUMMARY/ABSTRACT
Chemotherapy induced peripheral neuropathy is a common dose-limiting toxicity that can reduce therapeutic
effectiveness and impact quality of life for cancer patients. The overarching goal of this research is to
determine the molecular basis of chemotherapy-induced peripheral neuropathy to support the development of
targeted therapies to prevent and treat this toxicity. The proposed studies are based on a reverse translational
pharmacogenetic approach that uses genetic association findings to implicate critical pathways in peripheral
neuropathy. Recent genetic association and functional validation findings support a role for sphingosine-1-
phosphate (S1P) signaling in chemotherapy-induced neurotoxicity, which are consistent with previous studies
in rodent models. The studies proposed in this application will extend these findings and address a significant
gap in our knowledge of S1P signaling in target cells for toxicity, peripheral sensory neurons. The central
hypothesis that will be tested is that modulation of S1P signaling in peripheral sensory neurons by microtubule
targeting agents plays a critical role in their neurotoxicity. A human induced pluripotent stem cell derived
sensory neuron model of chemotherapy neurotoxicity (iPS-SNs) will be employed for all studies.
Pharmacological and genetic approaches will be used to modulate S1P signaling and interrogate
chemotherapy toxicity linked to this signaling pathway. The three aims are complementary and address
discrete functions of S1P. The first aim will investigate whether microtubule targeting agents alter sphingolipid
metabolism in sensory neurons and will link specific S1P receptors to cytoskeletal changes. The studies
proposed in the second aim will focus on Rho GTPase signaling downstream of S1P receptors and will
establish the S1P signaling axis that is critical for chemotherapy-induced changes in neurite structure and the
development of retraction bulbs. The third aim will use scRNA-seq and sc-ATACseq to elucidate whether
paclitaxel-induced changes in gene expression in iPS-SNs involve S1P effects on chromatin accessibility. The
ability of fingolimod, a multiple sclerosis therapy that targets S1P receptor signaling and is currently being
tested for prevention and treatment of paclitaxel-induced peripheral neuropathy, to protect against
chemotherapy-induced neurotoxicity will be examined. Collectively, these studies will reveal molecular
mechanisms underlying the axon degeneration that occurs in sensory neurons in response to microtubule
targeting agents and elucidate novel mechanisms for neuroprotection with fingolimod.

## Key facts

- **NIH application ID:** 10599009
- **Project number:** 3R01CA261068-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Deanna L Kroetz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $61,979
- **Award type:** 3
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599009

## Citation

> US National Institutes of Health, RePORTER application 10599009, Contribution of Nuclear S1P Signaling to Microtubule Targeting Agent-Induced Changes in Transcriptional Activity in Human iPS-SNs (3R01CA261068-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10599009. Licensed CC0.

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