Microvesicles as a Novel Transmitter for UVB-Induced Bioactive Products

微泡作为 UVB 诱导生物活性产品的新型发射体

• 批准号: 9386244
• 负责人: Ji Chen Bihl
• 金额: $ 19.54万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386244
• 关键词: Address; Agonist; Antioxidants; Ascorbic Acid; Attenuated; Biological; Blood; Blood Circulation; Bulla; Cell Line; Cells; Clinical; Dinoprostone; Disease; Epidermis; Epithelial Cells; Fever; Human; IL8 gene; Iatrogenesis; Immunosuppression; Inflammatory; Interleukin-10; Ionizing radiation; Link; Liquid substance; Measures; Mediating; Medical; Membrane; Metabolic; MicroRNAs; Modeling; Molecular; Mus; Nuclear; Null Lymphocytes; Oxides; PUVA Photochemotherapy; Patients; Pharmacology; Photobiology; Photosensitivity; Photosensitivity Disorders; Phototherapy; Platelet Activating Factor; Process; Production; Proteins; R-factor; Radiation therapy; Reactive Oxygen Species; Regulatory T-Lymphocyte; Signal Transduction; Signaling Molecule; Skin; Source; Stimulus; Suction; System; TNF gene; Techniques; Testing; Therapeutic; UVB induced; Ultraviolet B Radiation; Vesicle; Vitamin D; Vitamin E; chemotherapy; cigarette smoking; cytokine; design; environmental stressor; human subject; in vivo; keratinocyte; lipid mediator; mast cell; microvesicles; neoplastic cell; new therapeutic target; novel; particle; platelet activating factor receptor; response; stressor; ultraviolet

Project Summary 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 question in photobiology is how UVB-treated 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 generate high levels of the lipid mediator Platelet-activating factor (PAF) produced enzymatically and PAF-receptor (PAF-R) agonists produced non-enzymatically via reactive oxygen species. Recent studies using antioxidants and PAF-R-expressing/null cell lines have implicated involvement of PAF-R signaling in UVB generated MVP (UVB-MVP). Two aims are designed to test the hypothesis that UVB generates MVP in human skin in a PAF-dependent manner and transfers systemic effects via their carried potent signaling molecules. Aim 1 will determine if MVP are released from human skin following UVB and if this process is PAF-R dependent. We plan three complementary approaches. First, we will use human skin explants to induce multiple suction blisters with the blister fluid as source of MVP, and test effects of PAF-R antagonists/antioxidants. Second, we will induce suction blisters on human subjects with/without systemic antioxidants, and treat the blister roof with UVB. Finally, we will assess circulating MVP in vivo using paired blood draws (before/after phototherapy) from human patients undergoing whole body UVB treatment. Aim 2 will determine the bioactive agents in UVB-MVP. Both MVP and cells will be tested for three classes of agents: lipid mediators, protein cytokines and microRNAS. 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 systemic effects.

项目摘要 紫外线B（UVB）辐射对皮肤具有深远的影响，并产生全身性 从发烧到免疫抑制到维生素D产生的后果。仅作为UVB 穿透表皮，光生物学的主要问题是UVB处理的皮肤如何发送 全身信号。最近的研究表明，已知膜结合的小囊泡已知 随着微丝颗粒（MVP）从细胞中释放而响应各种应激源，可以作用 由于其携带核和细胞质成分的能力而引起的有效信号传导。 我们已经证明UVB会从上皮细胞和皮肤中释放MVP， 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）酶促生产的和PAF受体（PAF-R）激动剂 通过活性氧在非酶上产生。最近使用抗氧化剂的研究 PAF-R表达/无效的细胞系与PAF-R信号的参与涉及UVB 生成的MVP（UVB-MVP）。两个目标旨在检验UVB的假设 以PAF依赖性方式在人皮中生成MVP，并通过 它们带有有效的信号分子。 AIM 1将确定MVP是否从 UVB之后的人体皮肤，如果此过程取决于PAF-R。我们计划三个 互补方法。首先，我们将使用人类皮肤外植体诱导多个 带有水泡流体作为MVP来源的吸气水泡和PAF-R的测试效果 拮抗剂/抗氧化剂。其次，我们将引起人类主题的吸力水泡 使用/不具有全身性抗氧化剂，并用UVB处理水泡屋顶。最后，我们将评估 使用成对的血液抽血（光疗之前/之后）在体内循环MVP 接受全身UVB治疗的患者。 AIM 2将确定生物活性剂 在UVB-MVP中。 MVP和细胞都将进行三类药物的测试：脂质介质， 蛋白质细胞因子和microRNA。成功完成该项目将（i）解决 光生物学中的重要问题，即如何产生角质形成细胞特异性刺激 全身信号传导效应，（ii）提供药理机制来阻止UVB全身效应。