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.

抽象的 紫外线B（UVB）辐射对皮肤具有深远的影响，并产生发烧的全身后果 对维生素D产生的免疫抑制。由于UVB仅穿透表皮，因此一个主要的未回答 光生物学中的问题是UVB处理的表皮皮肤如何发送全身信号。最近的研究 表明膜结合的小囊泡被称为微囊泡颗粒（MVP），从细胞中释放 对各种压力源的响应可以充当有效的信号传导剂，因为它们具有核能和 细胞质成分。我们已经证明了UVB从上皮细胞中释放MVP， 皮肤，可以为UVB介导的全身信号传导提供潜在的机制。我们的小组和其他人 已经证明UVB辐射会产生高水平的脂质介体血小板激活因子 （PAF）通过反应性产生的酶促和PAF受体（PAFR）激动剂（PAFR）激动剂。 氧。我们正在进行的研究使用抗氧化剂和表达PAFR的/无效细胞系以及 酶酸鞘磷脂酶（ASMase）的药理/遗传抑制已牵涉到参与 PAFR信号传导导致UVB生成的MVP（UVB-MVP）中的ASMase激活。最后，我们提供 UVB-MVP没有大量蛋白质细胞因子，但携带生物活性PAF的证据 激动剂。我们有证据表明，代谢不稳定的PAF激动剂受到MVP的保护，而这些 生物活性脂质参与UVB的急性促炎和延迟免疫抑制作用。然而 关于如何生成UVB-MVP的知识差距以及是否可以利用这种新途径来治疗 光敏性疾病。两个目标旨在测试UVB在人类中产生MVP的假设 皮肤以PAF依赖性方式涉及ASMase，并通过其局部和全身效应转移 携带PAF激动剂。 AIM 1将使用体外细胞系以及鼠遗传和药理模型 确定UVB-MVP生成的机制。该目标将验证工具来定义UVB-的角色 MVP在UVB的急性促炎作用中，使用我们具有光敏性的鼠模型 先前证明的是PAF依赖性和单独的光敏鼠狼疮模型。 AIM 2将使用 离体皮肤外植体和体内人体受试者都可以测试人皮肤产生UVB-MVP的能力。 此外，我们将定义口服抗氧化剂和局部ASMase抑制剂治疗是否会阻止UVB-MVP 人类的产生和UVB介导的急性炎症。最后，我们将测试人类受试者是否表现出来 临床光敏性以增加UVB-MVP对UVB做出反应，如果局部ASMase抑制剂阻止了UVB UVB-MVP和夸张的皮肤反应。成功完成该项目将（i）解决 光生物学中的重要问题是关于角质形成细胞特异性刺激如何产生全身信号的问题 效果，（ii）提供药理机制来阻止UVB局部和全身效应。这些研究也有 理解其他促氧化应激源（包括电离辐射）的影响的意义。