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) 辐射对皮肤有深远影响，并会因发烧而产生全身性后果 免疫抑制影响维生素 D 的产生。由于 UVB 只能穿透表皮，因此一个主要的未解之谜 光生物学的问题是经过 UVB 处理的表皮如何发送系统信号。最近的研究有 表明，被称为微泡颗粒（MVP）的小膜结合囊泡从细胞中释放出来 对各种应激源的反应可以作为有效的信号剂，因为它们能够携带核和 细胞质成分。我们已经证明 UVB 会从上皮细胞中产生 MVP 释放，并且 皮肤，这可以为 UVB 介导的系统信号传导提供潜在机制。我们组和其他人 已经证明 UVB 辐射会产生高水平的脂质介质血小板激活因子 (PAF) 通过酶促反应产生，PAF 受体 (PAFR) 激动剂通过反应非酶促产生 氧物种。我们正在进行的研究使用抗氧化剂和 PAFR 表达/无效细胞系和 酸性鞘磷脂酶 (aSMase) 的药理学/遗传抑制可能涉及其中 PAFR 信号传导导致 UVB 生成 MVP (UVB-MVP) 中 aSMase 激活。最后，我们提供 有证据表明 UVB-MVP 不携带大量蛋白质细胞因子，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 旅行中受到保护，并且这些 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 UVB-MVP 如何产生以及是否可以利用这一新途径来治疗，存在知识差距 光敏性疾病。设计了两个目标来检验 UVB 在人体中产生 MVP 的假设 皮肤以 PAF 依赖性方式涉及 aSMase，并通过其传递局部和全身效应 携带PAF激动剂。目标 1 将使用体外细胞系和小鼠遗传和药理学模型 确定 UVB-MVP 的生成机制。该目标将验证定义 UVB 作用的工具 MVP 在 UVB 急性促炎作用中的应用，使用我们拥有的光敏小鼠模型 先前证明是 PAF 依赖性和单独的光敏小鼠狼疮模型。目标2将使用 离体皮肤外植体和体内人体受试者，以测试人类皮肤产生 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止 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 临床光敏性对 UVB 的反应会增加 UVB-MVP，并且如果局部 aSMase 抑制剂阻断 UVB-MVP 和夸张的皮肤反应。该项目的成功完成将 (i) 解决 光生物学中的一个重要问题是角质形成细胞特异性刺激如何产生系统信号 效应，(ii) 提供阻断 UVB 局部和全身效应的药理学机制。这些研究还有 对理解其他促氧化应激源（包括电离辐射）的影响的影响。