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UVB radiation-generated microvesicle particles as effectors for photosensitivity

Award Number: R01ES031087
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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UVB radiation-generated microvesicle particles as effectors for photosensitivity - Abstract Ultraviolet B (UVB) radiation has profound effects upon skin and generates systemic consequences from fever to immunosuppression to vitamin D production. As UVB only penetrates the epidermis, a major unanswered question in photobiology is how UVB-treated epidermal skin sends systemic signals. Recent studies have indicated that small membrane-bound vesicles known as microvesicle particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB generates MVP release from epithelial cells and skin, which could provide a potential mechanism for UVB-mediated systemic signaling. Our group and others have demonstrated that UVB radiation generates high levels of the lipid mediator Platelet-activating factor (PAF) produced enzymatically and PAF-receptor (PAFR) agonists produced non-enzymatically via reactive oxygen species. Our ongoing studies using antioxidants and PAFR-expressing/null cell lines and pharmacologic/genetic inhibition of the enzyme acid sphingomyelinase (aSMase) have implicated involvement of PAFR signaling resulting in aSMase activation in UVB generated MVP (UVB-MVP). Finally, we provide evidence that UVB-MVP do not carry significant amounts of protein cytokines, yet carry bioactive PAF agonists. We have evidence that metabolically labile PAF agonists are protected traveling in MVP and these bioactive lipids are involved in acute pro-inflammatory and delayed immunosuppressive effects of UVB. Yet knowledge gaps exist as to how UVB-MVP are generated and if this new pathway can be exploited to treat photosensitivity diseases. Two aims are designed to test the hypothesis that UVB generates MVP in human skin in a PAF-dependent manner involving aSMase and transfers both local and systemic effects via their carried PAF agonists. Aim 1 will use in vitro cell lines and murine genetic and pharmacologic models to determine the mechanisms of UVB-MVP generation. This aim will validate tools to define the roles of UVB- MVP in acute pro-inflammatory effects of UVB, using a murine model of photosensitivity that we have previously demonstrated is PAF-dependent and a separate photosensitive murine lupus model. Aim 2 will use both ex vivo skin explants and in vivo human subjects to test the ability of human skin to generate UVB-MVP. Moreover, we will define if oral antioxidants and topical aSMase inhibitor treatments will block UVB-MVP generation and UVB-mediated acute inflammation in humans. Finally, we will test if human subjects exhibiting clinical photosensitivity respond to UVB with increased UVB-MVP and if a topical aSMase inhibitor blocks the UVB-MVP and the exaggerated skin reactions. Successful completion of this project will (i) address an important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling effects, (ii) offer pharmacologic mechanisms to block UVB local and systemic effects. These studies also have implications for understanding the effects of other pro-oxidative stressors including ionizing radiation.


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: 2025 ( Subtotal = $337,500 )
2025	2025	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	000	5	2/14/2025	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2024 ( Subtotal = $337,500 )
2024	2024	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	001	4	1/26/2024	NON-COMPETING CONTINUATION	$337,500
2024	2024	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	002	4	4/17/2024	NON-COMPETING CONTINUATION	$0
2024	2024	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	003	4	5/20/2024	NON-COMPETING CONTINUATION	$0
2024	2023	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	000	3	12/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,500

Issue Date FY: 2023 ( Subtotal = $337,500 )
2023	2023	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	000	3	2/22/2023	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2022 ( Subtotal = $337,500 )
2022	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	000	2	1/13/2022	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2021 ( Subtotal = $337,500 )
2021	2021	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Environmental Health	000	1	3/26/2021	NEW	$337,500
														Subtotal = $337,500

Grand Total All Awards = $1,687,500

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UVB radiation-generated microvesicle particles as effectors for photosensitivity

Award Number: R01ES031087

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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