# Intracellular Functions of the Bioactive Sphingolipid Metabolites Sphingosine and Sphingosine-1-phosphate

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $417,698

## Abstract

PROJECT SUMMARY AND RELEVANCE
 The long-term goals of this project are to define the intracellular functions of the bioactive sphingolipid
metabolites, sphingosine-1-phosphate (S1P) and sphingosine. Most of the known actions of S1P, produced
intracellularly from sphingosine by two closely related sphingosine kinases, SphK1 and SphK2, are initiated by
signaling through S1P receptors. However, lower organisms have similar evolutionary conserved sphingolipid
metabolic enzymes and although their sphingolipid metabolites have important functions, they do not have S1P
receptors. Based on published and exciting preliminary results, our overarching hypothesis is that recruitment
of SphK1 to sphingosine-containing vesicles and conversion of sphingosine to S1P plays a critical role in
membrane trafficking, formation and functions of membrane contact sites between the endoplasmic reticulum
and late endosomes and lysosomes. These membrane contact sites are highly regulated regions of close
membrane apposition between organelles that serve as platforms for transfer and metabolism of lipids,
including cholesterol and sphingolipids, calcium homeostasis, and to ensure inter-organellar communication.
To test this concept, we propose the following specific aims: Aim 1. Identify the key steps in endocytic
trafficking and autophagic fluxes that rely on sphingosine to S1P conversion by SphK1; Aim 2. Evaluate the
role of the sphingosine/SphK1/S1P axis in regulation of ER-membrane contact sites and consequently on
cholesterol and sphingolipid metabolism; Aim 3. Determine the molecular mechanisms by which sphingolipid
metabolites regulate membrane trafficking and membrane contact sites and identify their intracellular targets.
This proposal will utilize several innovative technologies, including cutting edge electron microscopy and
systems-level live cell multispectral fluorescence-based spectroscopy imaging, as well as trifunctional
sphingosine click chemistry and state of the art sphingolipidomic mass spectrometry.
 The new conceptual groundwork in this proposal will alter the view of the enigmatic nature of
sphingolipid metabolite signaling and will reveal their ancient but understudied intracellular roles in regulation
of membrane dynamics and contact sites with the endoplasmic reticulum as sensors that integrate cell growth
signals and coordinate cholesterol and sphingolipid metabolism. This should also provide deeper
understanding of how perturbations of these fundamental biological processes contribute to human diseases.
!

## Key facts

- **NIH application ID:** 10070619
- **Project number:** 5R01GM043880-29
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** SARAH SPIEGEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,698
- **Award type:** 5
- **Project period:** 1990-04-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070619

## Citation

> US National Institutes of Health, RePORTER application 10070619, Intracellular Functions of the Bioactive Sphingolipid Metabolites Sphingosine and Sphingosine-1-phosphate (5R01GM043880-29). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10070619. Licensed CC0.

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