Targeting early ceramide elevation in pre-symptomatic eczema

特应性皮炎（AD）的患病率和发病率，最常见的湿疹类型，已经增加

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.