Targeting early ceramide elevation in pre-symptomatic eczema

针对症状前湿疹的早期神经酰胺升高

• 批准号: 10665481
• 负责人: Mitzi Nagarkatti
• 金额: $ 17.86万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665481
• 关键词: Antigens; Apoptosis; Atopic Dermatitis; Attenuated; Cells; Ceramides; Cutaneous; Disease; Disease Progression; Eczema; Effector Cell; Event; Human; Immune; Incidence; Inflammation; Lesion; Metabolism; Modeling; Pathogenesis; Pathogenicity; Pathway interactions; Phase; Prevalence; Reporting; Resveratrol; Sampling; Skin; Sphingolipids; T-Lymphocyte; burden of illness; chronic inflammatory skin; cytokine; dietary supplements; endoplasmic reticulum stress; mast cell; pre-clinical; prevent; recruit; skin barrier; skin disorder; skin lesion

The prevalence and incidence of atopic dermatitis (AD), most common type of eczema, have increased over the last several decades, as AD remains the most common chronic inflammatory skin disease. AD is characterized by widespread pruritic skin lesions, making it the skin disorder with the highest disease burden globally. The mechanisms leading to skin barrier disruption and overt lesions are ill defined. While some studies focus on T cell-derived cytokines as possible underlying effectors of disrupted skin, we reasoned that T cells may be preceded by mast cells as first-line effector cells as mast cells are skin resident immune cells facilitating T cell recruitment. Moreover, many AD studies are comparing features of lesional to neighboring non lesional skin samples, i.e., when the diseased state is already established, we used a preclinical human AD-like model to investigate the pathogenic events leading to overt lesions. We recently reported an early elevation of ceramide sphingolipids in skin samples treated with an AD-triggering antigen, compared to controls, that was driven by mast cells, enabling early cutaneous apoptosis through endoplasmic reticulum (ER) stress. In this proposal, we offer to investigate the contribution of ceramides and apoptosis in AD pathogenesis in another preclinical AD model and the effects of resveratrol, a natural compound, on restoring homeostatic ceramide metabolism to attenuate ER stress, apoptosis and subsequent loss of skin integrity. The objectives of this application are: To investigate the effects of resveratrol on early ceramide elevation and apoptosis in preclinical AD, and to study the impact of antigen exposure on human skin explants and the regulatory functions of resveratrol. We anticipate that our proposed studies will contribute to a better understanding of AD pathogenesis and the mechanisms of action of resveratrol. We are proposing that these studies will identify actionable pathogenic pathways preventing AD disease progression.

特应性皮炎（AD）的患病率和发病率是最常见的湿疹类型，已增加 在过去的几十年中，由于广告仍然是最常见的慢性炎症性皮肤病。广告是 以广泛的核皮肤病变为特征，使其成为疾病最高的皮肤疾病 全球负担。导致皮肤屏障破坏和明显病变的机制不明显。尽管 一些研究将重点侧重于T细胞衍生的细胞因子作为干扰皮肤的潜在效应子，我们 认为T细胞可以先于肥大细胞作为一线效应细胞，因为肥大细胞是皮肤 常驻免疫细胞促进T细胞募集。此外，许多广告研究正在比较 对邻近的非病变皮肤样本的病变，即，当已经建立病态状态时，我们 使用临床前的人类广告样模型来研究导致明显病变的致病事件。我们 最近报道了用A的皮肤样品中神经酰胺鞘脂的早期升高 与对照组相比，广告触发抗原是由肥大细胞驱动的，使得早期皮肤 通过内质网（ER）应激的凋亡。在此提案中，我们提出了调查 在另一个临床前AD模型中，神经酰胺和凋亡在AD发病机理中的贡献和 白藜芦醇是一种天然化合物的影响，对恢复稳态的神经酰胺代谢减弱 ER应力，凋亡和随后的皮肤完整性丧失。此应用程序的目标是： 研究白藜芦醇对临床前AD中神经酰胺升高和凋亡的影响，以及 研究抗原暴露对人体皮肤外植体的影响和白藜芦醇的调节功能。 我们预计我们的拟议研究将有助于更好地理解AD发病机理和 白藜芦醇作用机理。我们建议这些研究将确定可行的 致病途径可防止AD疾病进展。