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: 10550230
• 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/10550230
• 关键词: Acute; Address; Agonist; Antioxidants; Binding; Biochemical Reaction; Cell Line; Cells; Clinical; Cytoplasm; Disease; Dose; Enzyme Inhibition; Enzymes; Epidermis; Epithelial Cells; Exhibits; Fever; Generations; Genetic; Goals; Human; Imipramine; Immunosuppression; In Vitro; 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; PUVA Photochemotherapy; Pathologic; Pathway interactions; Penetration; Pharmacology; Photobiology; Photosensitivity; Photosensitivity Disorders; Phototherapy; Phototoxic Dermatitis; Platelet Activating Factor; Process; Production; Proteins; Reaction; Reactive Oxygen Species; Receptor Signaling; Regulatory T-Lymphocyte; 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; environmental stressor; genetic approach; human subject; in vivo; inhibitor; insight; keratinocyte; lipid mediator; mast cell; microvesicles; mouse model; novel; novel strategies; novel therapeutics; particle; pharmacologic; 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 紫外线B（UVB）辐射对皮肤有深远的影响，并产生发热的全身性后果 到免疫抑制到维生素D的产生。由于UVB只能穿透表皮， 光生物学中的一个问题是UVB处理的表皮皮肤如何发送系统信号。最近的研究 表明，小的膜结合囊泡被称为微泡颗粒（MVP）从细胞释放， 对各种应激源的反应可以作为有效的信号传导剂，这是由于它们能够携带核和 细胞质成分我们已经证明，UVB产生MVP从上皮细胞释放， 皮肤，这可能提供了一个潜在的机制UVB介导的系统信号。我们集团和其他 已经证明UVB辐射产生高水平的脂质介质血小板活化因子 (PAF)酶促产生和PAF受体（PAFR）激动剂通过反应性非酶促产生 氧物种。我们正在进行的研究使用抗氧化剂和PAFR表达/无效细胞系， 酸性鞘磷脂酶（aSMase）的药理学/遗传学抑制与 在UVB产生的MVP（UVB-MVP）中，PAFR信号传导导致aSM酶活化。最后，我们提供 证据表明，UVB-MVP不携带大量的蛋白质细胞因子，但携带生物活性PAF 激动剂我们有证据表明代谢不稳定的PAF激动剂在MVP中旅行时受到保护， 生物活性脂质参与UVB的急性促炎和延迟的免疫抑制作用。然而 关于UVB-MVP是如何产生的，以及这种新途径是否可以用于治疗， 光敏性疾病设计了两个目的来验证UVB在人体内产生MVP的假设 以涉及aSMase的PAF依赖性方式作用于皮肤，并通过其 携带PAF激动剂。目的1将使用体外细胞系和小鼠遗传和药理学模型， 确定UVB-MVP产生的机制。这一目标将验证定义UVB作用的工具， MVP在UVB的急性促炎作用中，使用我们已经建立的小鼠光敏性模型， 先前证明的是PAF依赖性和单独的光敏性鼠狼疮模型。目标2将使用 离体皮肤外植体和体内人类受试者两者来测试人类皮肤产生UVB-MVP的能力。 此外，我们将确定口服抗氧化剂和局部aSMase抑制剂治疗是否会阻断UVB-MVP， 产生和UVB介导的人类急性炎症。最后，我们将测试人类受试者是否表现出 UVB的临床光敏反应伴随着UVB-MVP的增加，如果局部aSMase抑制剂阻断了UVB， UVB MVP和夸张的皮肤反应。该项目的成功完成将（i）解决 光生物学中一个重要问题是角质细胞特异性刺激如何产生系统性信号 影响，（ii）提供药理学机制，以阻止UVB的局部和全身效应。这些研究也有 对理解包括电离辐射在内的其他促氧化应激因素的影响的影响。