# S1P signaling machinery in neuroimmune interactions

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $426,563

## Abstract

Project Summary/Abstract
Multiple sclerosis (MS) is an autoimmune disease that is characterized by demyelination and
inflammation in the central nervous system (CNS). In 2010 the FDA approved fingolimod as the first
orally available MS drug. It is phosphorylated in vivo, allowing it to bind four of the five known
sphingosine 1-phosphate (S1P) receptors (S1PR), S1P1, 3, 4, 5. The mechanism of action (MOA) of
fingolimod in MS is thought to be through lymphocyte sequestration of pathogenic cells in the
secondary lymphoid organs via inactivation of S1P1. However, several lines of evidence including
studies using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), have
supported the existence of another MOA for fingolimod involving non-immune, CNS activities. We
will test the central hypothesis that each S1PR has a unique role in EAE development and progression
through regulating the immune and/or nervous system. We will apply an innovative approach, that
utilizes nuclear RNA-seq and reporter mice that specifically detect activity after EAE challenge that
has identified astrocytes, along with on a collection of S1P receptor knockout mice, to address three
Specific Aims: Aim 1) Determine S1PRs that exacerbate EAE, followed by revealing their roles in EAE
pathogenesis; focusing on S1P5 and S1P4; Aim 2)! Define VB12 homeostasis regulation by astrocyte S1P1
in EAE; and Aim 3)! Discover clinical relevancies of S1PR modulators in combination with VB12. This
proposal will provide groundbreaking discoveries of: 1) roles of immunological and neuronal S1P5 in
EAE pathogenesis, 2) new functions of S1P4 in T cell regulation and EAE development, 3) deciphering
S1PR signaling complexity in T cells and oligodendrocytes, 4) a novel MOA of fingolimod that
astrocyte S1P1 controls VB12 homeostasis in the CNS, and 5) a new therapeutic strategy, i.e., VB12
supplementation to fingolimod therapy. Moreover, our research demonstrates the biological and
clinical significance of S1P signaling in MS and neuroimmunology, along with public health
awareness of the importance of adequate vitamin B12 intake to prevent diseases and to maintain
overall health.

## Key facts

- **NIH application ID:** 10348764
- **Project number:** 5R01NS103940-05
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Yasuyuki Kihara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $426,563
- **Award type:** 5
- **Project period:** 2018-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348764

## Citation

> US National Institutes of Health, RePORTER application 10348764, S1P signaling machinery in neuroimmune interactions (5R01NS103940-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348764. Licensed CC0.

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