Targeting early ceramide elevation in pre-symptomatic eczema

特应性皮炎(AD)是最常见的湿疹类型，其患病率和发病率有所增加 在过去的几十年里，AS AD仍然是最常见的慢性炎症性皮肤病。广告是 以广泛的皮肤瘙痒为特点，使其成为发病率最高的皮肤病 全球范围内的负担。导致皮肤屏障破坏和显性损害的机制尚不清楚。而当 一些研究集中在T细胞衍生的细胞因子可能是皮肤破损的潜在效应因素，我们 T细胞可能先于肥大细胞作为第一线效应细胞，因为肥大细胞是皮肤 促进T细胞募集的常驻免疫细胞。此外，许多AD研究正在比较 皮损到邻近的非皮损皮肤样本，即当疾病状态已经确定时，我们 使用临床前人类类AD模型来调查导致明显损害的致病事件。我们 最近有报道称，服用安慰剂的皮肤样本中神经酰胺鞘脂早期升高 与对照组相比，由肥大细胞驱动的AD触发抗原使早期皮肤 内质网(ER)应激引起的细胞凋亡。在这份提案中，我们提出要调查 神经酰胺和细胞凋亡在另一种临床前AD模型中的作用 天然化合物白藜芦醇恢复神经酰胺代谢平衡的作用 内质网应激、细胞凋亡和随后的皮肤完整性丧失。本应用程序的目标是： 研究白藜芦醇对临床前期AD患者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移植的影响及白藜芦醇的调节作用。 我们预计，我们提出的研究将有助于更好地了解AD的发病机制和 白藜芦醇的作用机制。我们建议这些研究将确定可行的 阻止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.