UVB radiation-generated microvesicle particles as effectors for photosensitivity

UVB 辐射产生的微泡颗粒作为光敏效应器

• 批准号: 10378684
• 负责人: Yanfang Chen
• 金额: $ 33.75万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378684
• 关键词: Acute; Address; Agonist; Antioxidants; Biochemical Reaction; Cell Line; Cells; Clinical; Disease; Dose; Enzyme Inhibition; Enzymes; Epidermis; Epithelial Cells; Exhibits; Fever; Generations; Genetic; Goals; Human; Imipramine; Immunosuppression; In Vitro; Inbred MRL lpr Mice; Individual; Inflammation; Inflammatory; Inflammatory Response; Ionizing radiation; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Lipids; Lupus; Measures; Mediating; Medical; Membrane; Metabolic; Modeling; Molecular; Mus; Nuclear; Null Lymphocytes; Oral; Oxides; Pathologic; Pathway interactions; Pharmacology; Photobiology; Photosensitivity; Photosensitivity Disorders; Phototherapy; Phototoxic Dermatitis; Platelet Activating Factor; Process; Production; Proteins; Reaction; Reactive Oxygen Species; Receptor Signaling; Role; Signal Transduction; Signal Transduction Pathway; Skin; Stimulus; Techniques; Testing; Therapeutic; Travel; UV response; UVB induced; Ultraviolet B Radiation; Vesicle; Vitamin D; XPA gene; acid sphingomyelinase; cytokine; design; genetic approach; human subject; in vivo; inhibitor; insight; keratinocyte; lipid mediator; mast cell; microvesicles; mouse model; novel; novel strategies; novel therapeutics; particle; platelet activating factor receptor; response; stressor; tool; ultraviolet

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.

摘要