# Mechanisms of hematopoietic acute radiation syndrome induction and radioprotection through sphingosine 1-phosphate receptor 1 signal modulation

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $487,500

## Abstract

Significance: Ionizing radiation (IR) is a frequently utilized treatment modality for a variety of cancers,
including leukemias, cancers in the pelvic region (e.g. cervical, testicular), and brain or bone malignancies.
However, detrimental effects on normal bone marrow (BM) hematopoietic stem and progenitor cells (HSPC)
are a major limitation of radiotherapy. We are also faced with the increasing threat of terrorist or military
utilization of radioactive/nuclear weapons. Despite intense investigation and need, there is no therapy FDA-
approved for broad clinical or emergency hematopoietic radioprotection. Sphingosine 1-phosphate (S1P) is a
simple phospholipid found in high nM to low µM concentrations in blood and signals via specific G-protein
coupled receptors. The best characterized is S1P₁, the target of an FDA-approved multiple sclerosis drug,
FTY720 (Gilenya). We have recently shown that S1P can signal via S1P₁1 on BM lymphocyte progenitors to
regulate their proliferation, but roles for S1P₁ signaling in other HSPC populations, at homeostasis or under
stress conditions, are unknown. Preliminary data: With the use of a novel mouse model that reports S1P₁
activation as nuclear GFP expression, we found that exposure to a single dose of 750 rad gIR results in
increased HSPC S1P₁ expression and signaling. A mouse model of inducible genetic S1P₁ over-expression
(S1P1Tg) yields a BM failure phenotype similar to that induced with ≤ 900 rad gIR. Administration of clinically
relevant doses of FTY720 as little as 2h pre-IR protects from BM failure and subsequent lethality, as does
genetic S1P1KO. Based on these data, we hypothesize that increased S1P1 expression and signaling are
an HSPC-intrinsic mechanism driving gIR-induced cytotoxicity and apoptosis. DNA damage,
mitochondrial dysfunction, and reactive oxygen species are the primary consequences of gIR that trigger cell
death, but how S1P₁ signaling plays a role in these effector pathways is unknown. In the following Specific
Aims, we will utilize this novel in vivo model of GPCR signaling and models of inducible S1P1Tg and S1P1KO in
ex vivo hematopoiesis and in vivo settings to critically examine the concept that the S1P-S1P1 signaling axis is
a major pathway governing these HSPC apoptotic responses to γ-IR: 1) Determine the mechanisms by which
gIR induces hematopoietic S1P₁1 expression, signaling, and subsequent apoptosis; 2) Determine the
mechanism whereby increased S1P₁ signaling leads to HSPC death and BM failure; 3) Determine if the
radioprotective effect of S1P₁ antagonism leads to increased long-term survival and if there is a coincident
increase in leukemia incidence. These studies are likely to have a large overall impact by expanding our
understanding of fundamental HSPC apoptotic mechanisms and responses to γIR, and characterizing a
novel, therapeutically tractable signaling pathway as a potential target for prevention of radiation-
induced hematotoxicity.

## Key facts

- **NIH application ID:** 10200131
- **Project number:** 5R01HL141880-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Victoria Alison Blaho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 2018-09-07 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200131

## Citation

> US National Institutes of Health, RePORTER application 10200131, Mechanisms of hematopoietic acute radiation syndrome induction and radioprotection through sphingosine 1-phosphate receptor 1 signal modulation (5R01HL141880-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200131. Licensed CC0.

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