Targeting early ceramide elevation in pre-symptomatic eczema

特应性皮炎（AD）是湿疹中最常见的一种，其患病率和发病率呈上升趋势 在过去的几十年里，AD仍然是最常见的慢性炎症性皮肤病。AD是 以广泛的皮炎皮肤病变为特征，使其成为疾病发生率最高的皮肤病 全球负担。导致皮肤屏障破坏和明显病变的机制尚不清楚。而 一些研究集中在T细胞衍生的细胞因子作为破坏皮肤的潜在效应物，我们 我的理由是，T细胞之前可能是肥大细胞作为第一线效应细胞，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 损伤皮肤样本与相邻的非损伤皮肤样本，即，当疾病状态已经建立时，我们 使用临床前人类AD样模型研究导致明显病变的致病事件。我们 最近报道了在用抗氧化剂治疗的皮肤样品中神经酰胺鞘脂的早期升高， 与对照组相比，由肥大细胞驱动的AD触发抗原， 通过内质网（ER）应激引起细胞凋亡。在这份提案中，我们提议调查 神经酰胺和细胞凋亡在另一种临床前AD模型中AD发病机制中的作用， 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， ER应激、细胞凋亡和随后的皮肤完整性丧失。本申请的目的是： 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， 研究抗原暴露对人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的发病机制， 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 预防AD疾病进展的致病途径。

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.