The Immunoregulatory Effects of Electrophilic Fatty Acids on Psoriasis

 描述(申请人提供)：牛皮癣是一种皮肤自身免疫性疾病，影响大约2%的人口，无法治愈。它是一种细胞介导的疾病，其中核因子-B调节的细胞因子表达和IL-23/IL-17轴是参与发病的关键易感途径。因此，针对这些通路的治疗将是非常有利的。天然产生的亲电硝基脂肪酸，如硝基油酸(OA-NO2)，是不饱和脂肪酸的硝化产物，介导抗炎、抗氧化和细胞保护反应。硝基脂肪酸的治疗潜力已在几种活体小鼠炎症性疾病模型中得到证实。在这一点上，OA-NO2抑制了NF-B信号转导，从而抑制了促炎反应，并将银屑病区分为亲电硝基脂肪酸治疗的极佳候选者。正在进行的研究表明，皮下注射OA-NO2在小鼠模型中抑制和治疗接触性超敏反应(CHS)。因此，我们假设，以亲电脂肪酸为靶点的皮肤免疫系统将抑制牛皮癣的皮肤炎过程。我们提出的研究将确定和区分在SC注射亲电脂肪酸治疗炎症性皮肤病后诱导皮肤抗炎免疫反应的机制。这项临床前研究的目标是 建议通过检查具体目标使这类新药能够翻译应用于治疗牛皮癣和其他炎症性皮肤病：目的1.确定OA-NO2在ACD小鼠模型中诱导的保护机制。目的2.检测OA-NO2对银屑病的抗炎作用。亲电脂肪酸的保守性支持了我们提出的临床前研究的翻译价值，并提供了一个机会，通过结合人类和小鼠炎症模型，包括人源化的小鼠异种移植模型和K14-血管内皮生长因子小鼠模型，利用独特的创新方法。这些研究将确定亲电脂肪酸在皮肤中的抗炎和保护作用的潜在机制。它们将揭示皮肤中的内源性脂质信号机制，并将加深我们对亲电性NO2-FA在皮肤免疫中的作用的理解。最后，这些研究将为亲电硝基脂肪酸治疗皮肤病的治疗发展提供信息。

 DESCRIPTION (provided by applicant): Psoriasis is a cutaneous autoimmune disease that affects approximately 2% of the population and has no cure. It is a cell-mediated disease in which NF-¿B-regulated cytokine expression and the IL-23/IL-17 axis are key susceptibility pathways involved in pathogenesis. Thus, therapeutics targeting these pathways would be highly advantageous. Naturally occurring electrophilic nitro-fatty acids, such as nitro-oleic acid (OA-NO2), are nitration products of unsaturated fatty acids that mediate anti-inflammatory, antioxidant, and cytoprotective reactions. The therapeutic potential of nitro-fatty acids has been demonstrated in several in vivo murine models of inflammatory disease. In this regard, OA-NO2 inhibits NF-B signal transduction, thereby suppressing pro- inflammatory responses and distinguishing psoriasis as an excellent candidate for electrophilic nitro-fatty acid therapies. Ongoing studies demonstrate that subcutaneous (SC) injections of OA-NO2 inhibit and treat contact hypersensitivity (CHS) in a murine model. Thus, we hypothesize that targeting the skin immune system with electrophilic fatty acids will suppress cutaneous inflammatory processes central to psoriasis. The studies we propose will identify and distinguish the mechanisms involved in inducing the cutaneous anti- inflammatory immune response observed following SC injections of electrophilic fatty acids in inflammatory skin diseases. The goal of this preclinical proposal is to enable translational application of this new class of drugs for the treatment of psoriasis and other inflammatory skin diseases by examining the specific aims: Aim 1. Define the protective mechanisms induced by OA-NO2 in a murine model of ACD. Aim 2. Determine the anti-inflammatory effects of OA-NO2 on psoriasis. The conserved nature of electrophilic fatty acids supports the translational value of the preclinical studies we propose and provide an opportunity to utilize a unique and innovative approach by combing both human and murine inflammatory models, including the humanized mouse xenograft model and the K14-VEGF murine model. These studies will identify the mechanisms underlying the anti-inflammatory and protective effects of electrophilic fatty acids in the skin. They will reveal endogenous lipid signaling mechanisms in the skin and will improve our understanding of the function of electrophilic NO2-FA in skin immunity. Finally, these studies will inform the therapeutic development of electrophilic nitro-fatty acids for the treatment of skin diseases.