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.

最常见的湿疹类型特应性皮炎 (AD) 的患病率和发病率有所增加 在过去的几十年里，AD 仍然是最常见的慢性炎症性皮肤病。广告是 其特点是广泛的瘙痒性皮肤损害，使其成为发病率最高的皮肤病 全球的负担。导致皮肤屏障破坏和明显损伤的机制尚不明确。尽管 一些研究重点关注 T 细胞衍生的细胞因子作为受损皮肤的潜在效应物，我们 推测 T 细胞之前可能是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 AD 研究正在比较以下特征： 病变到邻近的非病变皮肤样本，即，当病变状态已经建立时，我们 使用临床前人类 AD 样模型来研究导致明显病变的致病事件。我们 最近报道了经过处理的皮肤样本中神经酰胺鞘脂的早期升高 与对照相比，AD 触发抗原由肥大细胞驱动，能够早期皮肤 通过内质网（ER）应激进行细胞凋亡。在本提案中，我们提议调查 另一种临床前 AD 模型中神经酰胺和细胞凋亡在 AD 发病机制中的贡献 白藜芦醇（一种天然化合物）对恢复稳态神经酰胺代谢的影响减弱 内质网应激、细胞凋亡以及随后的皮肤完整性丧失。该应用程序的目标是： 研究白藜芦醇对临床前 AD 早期神经酰胺升高和细胞凋亡的影响，并 研究抗原暴露对人类皮肤外植体的影响以及白藜芦醇的调节功能。 我们预计我们提出的研究将有助于更好地了解 AD 发病机制和 白藜芦醇的作用机制。我们建议这些研究将确定可采取行动的 阻止 AD 疾病进展的致病途径。