The role of TNF-Alpha in cutaneous integrity

TNF-α 在皮肤完整性中的作用

• 批准号: 8441176
• 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/8441176
• 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; 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，这种细胞因子在光损伤中被诱导，这是一个日益严重的问题，因为紫外线被用于治疗，并且因为我们的部队正在服役或已经从世界上阳光特别强烈的地区返回。 TNFa过量与短期损伤（晒伤）相关，但也与严重的长期问题相关，例如皮肤的过早老化和脆弱性、光敏性自身免疫性疾病、癌前病变和皮肤癌。在另一个方向，抑制TNFa的新药被广泛用于治疗退伍军人牛皮癣，类风湿性关节炎和炎症性肠病。不幸的是，TNFa抑制也促进皮肤癌，并且由于这种细胞因子在促进透明质酸合成中的正常作用，可能干扰皮肤完整性。基于这些数据，我们的总体假设是皮肤中过多或过少的TNFa会损害皮肤的健康和完整性。我们提出表征皮肤光损伤期间由TNF α过量引起的介导胶原损失的过程（目的1），确定UV暴露期间TNF α过量产生的分子机制（目的2），最重要的是，评估在TNF α抑制和/或UV治疗期间人类皮肤基质破坏的潜在机制（目的3）。 目的1：表征介导由过量TNF α诱导的胶原损失的过程。我们将通过比较单独用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来确定TNF α在UV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，我们将描述它们在体内UV诱导的胶原蛋白损失，MMP诱导和其他炎症细胞的招募中的作用。 目的2：UVB诱导过量TNF α的分子机制。我们先前发现UVB和IL-1a在诱导TNF α基因转录中具有强烈的波长特异性协同作用，并且这种协同作用依赖于UVB对AP-1的激活和IL-1a对NF κ B的激活。在这里，我们将使用mega-DNase I超敏反应分析（MDHA）的内源性TNF α基因，以发现远端顺式作用的控制序列。TNF α启动子/CAT报告基因构建体将用于重现对UVB+IL-1 α的协同应答，精确定位调节位点，并确定它们是否直接结合NF κ B或由NF κ B诱导的因子。 目的3：暴露于急性UV和/或TNF α慢性阻断的退伍军人中皮肤基质破坏的机制。我们将扩展目标1的发现，以研究人体皮肤中胶原蛋白损失的机制。将检查来自用和不用UV、用和不用TNFa阻断剂治疗的银屑病患者的皮肤中的MMP和炎性细胞，并将其与我们在小鼠中的发现相关联。UV疗法和TNFa抑制剂广泛用于退伍军人，可能会干扰皮肤完整性。我们将研究这两种治疗方式对真皮厚度、I型胶原和HAS 2表达的影响。 总体而言，这些目标将提供对TNF α相关胶原损失的机制、TNF α响应于UV募集到皮肤中的炎性浸润的性质、UV如何诱导TNF α表达以及在改变TNF α的治疗期间对人类皮肤的损伤的机制的更好理解。这些信息将有助于评估和开发潜在的干预措施，以防止这些广泛的和破坏性的皮肤变化。