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

Award Number: R01HL141880
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$4,389 )
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	5	3/28/2024	NON-COMPETING CONTINUATION	-$4,389
														Subtotal = -$4,389

Issue Date FY: 2022 ( Subtotal = $487,500 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	5	6/23/2022	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2021 ( Subtotal = $487,500 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	4	6/25/2021	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2020 ( Subtotal = $487,500 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	3	6/24/2020	NON-COMPETING CONTINUATION	$0
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	3	6/22/2020	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2019 ( Subtotal = $487,500 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	2	6/25/2019	NON-COMPETING CONTINUATION	$487,500
2019	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	1	5/20/2019	NEW	$0
														Subtotal = $487,500

Issue Date FY: 2018 ( Subtotal = $487,500 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	1	9/7/2018	NEW	$487,500
														Subtotal = $487,500

Grand Total All Awards = $2,433,111

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

Award Number: R01HL141880

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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