The Immunoregulatory Effects of Electrophilic Fatty Acids on Psoriasis

描述（由申请人提供）：银屑病是一种皮肤自身免疫性疾病，影响约2%的人口，并没有治愈。它是一种细胞介导的疾病，其中NF-κ B调节的细胞因子表达和IL-23/IL-17轴是参与发病机制的关键易感性途径。因此，靶向这些途径的治疗剂将是非常有利的。天然存在的亲电硝基脂肪酸，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炎症性疾病的体内鼠模型中得到证实。在这方面，OA-NO2抑制NF-κB信号转导，从而抑制促炎反应并将银屑病区分为亲电硝基脂肪酸疗法的优秀候选者。正在进行的研究表明，皮下（SC）注射OA-NO2可抑制和治疗鼠模型中的接触性超敏反应（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银屑病的皮肤炎症过程。我们提出的研究将确定和区分在炎症性皮肤病中SC注射亲电脂肪酸后观察到的诱导皮肤抗炎免疫应答的机制。该临床前提案的目标是通过检查特定目标，使这类新型药物能够转化应用于治疗银屑病和其他炎症性皮肤病：目标1。定义在ACD小鼠模型中由OA-NO2诱导的保护机制。目标二。确定OA-NO2对银屑病的抗炎作用。亲电脂肪酸的保守性支持我们提出的临床前研究的转化价值，并通过结合人和鼠炎症模型（包括人源化小鼠异种移植模型和K14-VEGF鼠模型）提供了利用独特创新方法的机会。这些研究将确定皮肤中亲电脂肪酸抗炎和保护作用的机制。它们将揭示皮肤中的内源性脂质信号传导机制，并将提高我们对亲电子NO2-FA在皮肤免疫中的功能的理解。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-κB-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-κB 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.