The role of TNF-Alpha in cutaneous integrity

TNF-α 在皮肤完整性中的作用

• 批准号: 8803242
• 负责人: VICTORIA P WERTH
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803242
• 关键词: Acute; Area; Autoimmune Diseases; Binding; Biopsy; Cancerous; Cells; Chronic; Collagen; Collagen Fibril; Collagen Type I; Critical Pathways; Cutaneous; Data; Deoxyribonuclease I; Dermal; Dermis; Development; Distal; Enzymes; Epidermis; Etanercept; Evaluation; Exposure to; Fibroblasts; Genes; Genetic Transcription; Glycosaminoglycans; Goals; Health; Home environment; Human; Hyaluronan; Hyaluronic Acid; Hypersensitivity; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Interleukin-1 alpha; Intervention; Lesion; MMP8 gene; Matrix Metalloproteinases; Mediating; Medicine; Methods; Modality; Molecular; Mus; NF-kappa B; Nature; Other Genetics; Patients; Play; Population; Premature aging syndrome; Process; Psoriasis; Recruitment Activity; Reporter; Rheumatoid Arthritis; Role; Site; Skin; Skin Cancer; Source; Sunburn; Sunlight; TNF gene; Thick; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Veterans; Work; base; cell type; collagenase; cytokine; human TNF protein; in vivo; inhibitor/antagonist; insight; mast cell; prevent; promoter; public health relevance; resilience; response; ultraviolet damage

DESCRIPTION (provided by applicant): Veterans suffer from several common skin conditions in which TNFa plays a key role. For example, this cytokine is induced in photodamage, which is a growing problem because UV is used therapeutically, and because our troops are serving or have returned from areas of the world where sunlight is particularly intense. TNFa excess is associated with short-term damage (sunburn), but also serious long-term problems, such as premature aging and fragility of the skin, photosensitive autoimmune diseases, pre-cancerous lesions, and skin cancer. In the other direction, new medicines to inhibit TNFa are widely used therapeutically in Veterans with psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Unfortunately, TNFa inhibition also promotes skin cancers and may interfere with skin integrity owing to the normal role of this cytokine in promoting hyaluronan synthesis. Based on these data, our overall hypothesis is that too much or too little TNFa in the skin harms cutaneous health and integrity. We propose to characterize the processes mediating collagen loss caused by TNFa excess during cutaneous photodamage (Aim 1), determine the molecular mechanisms for TNFa overproduction during UV exposure (Aim 2), and most importantly, evaluate potential mechanisms for skin matrix disruption in humans during therapy with TNFa inhibition and/or UV (Aim 3). Aim 1: Characterization of processes mediating the collagen loss induced by excess TNFa. We will determine the roles of TNFa in UV-induced collagen change and inflammation by comparing the activation of collagenases and related enzymes, as well as populations of infiltrating cells, in th skin of mice treated with UVB alone versus UVB+etanercept. Using genetic and other methods to manipulate specific types of infiltrating immune cells, we will characterize their roles in vivoin UV-induced collagen loss, MMP induction, and recruitment of other inflammatory cells. Aim 2: Molecular mechanisms by which UVB induces excess TNFa. We previously found strong, wavelength-specific synergy between UVB and IL-1a in the induction of TNFa gene transcription and that this synergy depends on activation of AP-1 by UVB and NFKB by IL-1a. Here, we will use mega-DNase I hypersensitivity analysis (MDHA) of the endogenous TNFa gene to discover distal cis-acting control sequences. TNFa promoter/CAT reporter constructs will be used to recapitulate the synergistic response to UVB+IL-1a, pinpoint regulatory sites, and determine if they bind NFKB directly or factors induced by NFKB. Aim 3: Mechanisms of cutaneous matrix disruption in Veterans exposed to acute UV and/or chronic blockade of TNFa. We will extend the findings from Aim 1 to examine the mechanism of collagen loss in human skin. MMPs and inflammatory cells in skin from patients with psoriasis treated with and without UV, with and without TNFa blockade, will be examined and correlated with our findings in mice. UV therapy and TNFa inhibitors are widely used in Veterans and may interfere with cutaneous integrity. We will examine the effects of these two treatment modalities on dermal thickness, type I collagen, and HAS2 expression. Overall, these Aims will provide a better understanding of the mechanism of TNFa-related collagen loss, nature of the inflammatory infiltrate recruited by TNFa into skin in response to UV, how UV induces TNFa expression, and the mechanisms for damage to human skin during therapies that alter TNFa. This information will facilitate evaluation and development of potential interventions to prevent these extensive and destructive changes in skin.

描述（由申请人提供）： 退伍军人患有几种常见的皮肤病，其中 TNFa 起着关键作用。例如，这种细胞因子是在光损伤中诱导的，这是一个日益严重的问题，因为紫外线用于治疗，而且我们的部队正在世界上阳光特别强烈的地区服役或返回。 TNFa 过量与短期损伤（晒伤）有关，但也与严重的长期问题有关，例如皮肤过早衰老和脆弱、光敏性自身免疫性疾病、癌前病变和皮肤癌。另一方面，抑制 TNFa 的新药广泛用于治疗患有牛皮癣、类风湿性关节炎和炎症性肠病的退伍军人。不幸的是，由于这种细胞因子在促进透明质酸合成中的正常作用，TNFa 抑制也会促进皮肤癌，并可能干扰皮肤完整性。根据这些数据，我们的总体假设是皮肤中的 TNFa 过多或过少都会损害皮肤的健康和完整性。我们建议描述皮肤光损伤期间 TNFa 过量引起的胶原蛋白损失的介导过程（目标 1），确定紫外线照射期间 TNFa 过量产生的分子机制（目标 2），最重要的是，评估 TNFa 抑制和/或紫外线治疗期间人类皮肤基质破坏的潜在机制（目标 3）。 目标 1：表征过量 TNFa 引起的胶原蛋白损失的介导过程。我们将通过比较单独使用 UVB 与 UVB+依那西普治疗的小鼠皮肤中胶原酶和相关酶的活化以及浸润细胞群，确定 TNFa 在紫外线诱导的胶原蛋白变化和炎症中的作用。使用遗传和其他方法来操纵特定类型的浸润免疫细胞，我们将表征它们在体内紫外线诱导的胶原蛋白损失、MMP 诱导和其他炎症细胞招募中的作用。 目标 2：UVB 诱导过量 TNFa 的分子机制。我们之前发现 UVB 和 IL-1a 在诱导 TNFa 基因转录方面存在强烈的、波长特异性的协同作用，并且这种协同作用取决于 UVB 激活 AP-1 和 IL-1a 激活 NFKB。在这里，我们将使用内源性 TNFa 基因的大型 DNase I 超敏分析 (MDHA) 来发现远端顺式作用控制序列。 TNFa 启动子/CAT 报告基因构建体将用于重现对 UVB+IL-1a 的协同反应，精确定位调节位点，并确定它们是否直接结合 NFKB 或由 NFKB 诱导的因子。 目标 3：暴露于急性紫外线和/或慢性 TNFa 阻断的退伍军人皮肤基质破坏的机制。我们将扩展目标 1 的发现来研究人类皮肤中胶原蛋白流失的机制。将检查接受或不接受紫外线治疗、接受或不接受 TNFa 阻断治疗的银屑病患者皮肤中的 MMP 和炎症细胞，并将其与我们在小鼠中的发现相关联。紫外线疗法和 TNFa 抑制剂广泛用于退伍军人，可能会干扰皮肤的完整性。我们将检查这两种治疗方式对真皮厚度、I 型胶原蛋白和 HAS2 表达的影响。 总体而言，这些目标将有助于更好地了解 TNFa 相关胶原蛋白损失的机制、TNFa 响应紫外线而招募到皮肤的炎症浸润的性质、紫外线如何诱导 TNFa 表达，以及改变 TNFa 的治疗过程中对人类皮肤造成损害的机制。这些信息将有助于评估和开发潜在的干预措施，以防止皮肤发生这些广泛的破坏性变化。