Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis

E-FABP在银屑病发病机制中的免疫调节机制

• 批准号: 10459902
• 负责人: Bing Li
• 金额: $ 38.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459902
• 关键词: Abnormal Keratinocyte; Address; Cell physiology; Cellular Metabolic Process; Chronic; Data; Dendritic Cells; Development; High Fat Diet; Human; Imiquimod; Immune; Immune signaling; Inflammation; Inflammatory; Knockout Mice; Link; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Protein Deficiency; Psoriasis; Role; Sampling; Severities; Signal Transduction; Skin; Skin Tissue; Testing; Wild Type Mouse; adaptive immune response; chronic inflammatory skin; conditional knockout; design; diet-induced obesity; experimental study; fatty acid-binding proteins; immunoregulation; innate immune function; interleukin-23; keratinocyte; keratinocyte differentiation; link protein; mouse model; novel; novel strategies; oxidation; protein expression; response; sensor; skin disorder; treatment strategy; Abnormal Keratinocyte; Address; Cell physiology; Cellular Metabolic Process; Chronic; Data; Dendritic Cells; Development; High Fat Diet; Human; Imiquimod; Immune; Immune signaling; Inflammation; Inflammatory; Knockout Mice; Link; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Protein Deficiency; Psoriasis; Role; Sampling; Severities; Signal Transduction; Skin; Skin Tissue; Testing; Wild Type Mouse; adaptive immune response; chronic inflammatory skin; conditional knockout; design; diet-induced obesity; experimental study; fatty acid-binding proteins; immunoregulation; innate immune function; interleukin-23; keratinocyte; keratinocyte differentiation; link protein; mouse model; novel; novel strategies; oxidation; protein expression; response; sensor; skin disorder; treatment strategy

Summary Psoriasis is the most prevalent and intractable immune-mediated chronic inflammatory skin disease. It is clear that dendritic cells (DCs) and keratinocytes in the skin tissues play a central role in the pathogenesis of psoriasis. The objectives of this proposal are to determine the role of epidermal fatty acid binding protein (E- FABP) in promoting psoriasis pathogenesis through simultaneously targeting both DCs and keratinocytes and in linking obesity-associated psoriasis development. E-FABP, first cloned in psoriatic skin tissues (also known as psoriasis associated FABP), has been identified as a critical regulator of both metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP is greatly upregulated in the skin tissue from patients with psoriasis. Intriguingly, deficiency of E-FABP confers protection from imiquimod (IMQ) or IL-23- induced psoriasis-like inflammation in mouse models. While obesity is associated with increased severity of psoriasis and poor responses to therapy, the underlying mechanisms between obesity and psoriasis are unknown. While high fat diet (HFD) increases E-FABP expression in both DCs and keratinocytes and promotes obesity-associated chronic skin inflammation in wild type mice, E-FABP deficiency protects mice against HFD- induced effects. All these data suggest that E-FABP may link obesity and psoriasis via regulating metabolism and function of DCs and keratinocytes. Thus, we hypothesize that E-FABP, as a new link underlying the obesity-psoriasis association, promotes psoriasis pathogenesis through enhancing cellular metabolism and function of both DCs and keratinocytes. Therefore, targeting E-FABP may represent a novel strategy for psoriasis therapy. We design three specific aims (Figure A) to address our hypotheses. Specific Aim 1 will address how E-FABP regulates DC metabolism and function in psoriasis. We hypothesize that E-FABP links FA metabolism and innate immune signaling in DCs and bridges innate and adaptive immune responses for psoriasis pathogenesis. Specific Aim 2 will determine how E-FABP promotes keratinocyte aberrant metabolism and differentiation in psoriasis. We will design experiments to test the hypothesis that E-FABP expression in keratinocytes mediates innate signal-induced metabolic changes that are critical for abnormal keratinocyte differentiation. Specific Aim 3 will examine whether E-FABP links the obesity/psoriasis association using our unique E-FABP global and conditional knock out mouse models and samples from psoriasis patients. In summary, this proposal will demonstrate a novel mechanism by which E-FABP promotes psoriasis pathogenesis and links obesity-associated psoriasis development. Thus, targeting E-FABP may offer a novel strategy for treatment of psoriasis and other inflammatory skin disorders.

概括 牛皮癣是最普遍，最棘手的免疫介导的慢性炎性皮肤病。很明显 皮肤组织中的树突状细胞（DCS）和角质形成细胞在 银屑病。该提案的目标是确定表皮脂肪酸结合蛋白的作用（e- fabp）通过同时靶向DC和角质形成细胞和角质形成细胞，促进牛皮癣发病机理 在连接与肥胖相关的牛皮癣的发展中。 E-FABP，首先克隆在银屑病皮肤组织中（也已知 作为牛皮癣相关的FABP），已被确定为代谢和炎症的关键调节剂 途径。我们的初步研究表明，从 牛皮癣患者。有趣的是，E-FABP的缺乏赋予了免受咪喹莫德（IMQ）或IL-23-的保护 小鼠模型中诱导的牛皮癣样炎症。肥胖与严重程度增加有关 牛皮癣和对治疗的反应不良，肥胖和牛皮癣之间的潜在机制是 未知。高脂饮食（HFD）增加了DC和角质形成细胞的E-FABP表达，并促进 野生型小鼠肥胖相关的慢性皮肤炎症，电子可能性缺乏可保护小鼠免受HFD-的影响 诱导的效果。所有这些数据表明，电子可能会通过调节代谢来连接肥胖和牛皮癣 DC和角质形成细胞的功能。因此，我们假设该电子企业是一个新链接 肥胖-PSORIASIS相关，通过增强细胞代谢和 DC和角质形成细胞的功能。因此，针对电子-FABP可能代表了一种新颖的策略 牛皮癣治疗。我们设计了三个特定目标（图A）来解决我们的假设。具体目标1将 探讨电子-FABP如何调节牛皮癣的直流代谢和功能。我们假设E-FABP链接 FA代谢和天生的免疫信号传导和桥梁先天和适应性免疫反应 牛皮癣发病机理。特定的目标2将决定e-FABP如何促进角质形细胞异常 牛皮癣的代谢和分化。我们将设计实验以检验电子-FABP的假设 角质形成细胞中的表达介导了先天信号诱导的代谢变化，这对于异常至关重要 角质形成细胞分化。特定目标3将检查电子fabp是否链接肥胖/牛皮癣 使用我们独特的E-FABP全局和条件敲除鼠标模型和样本中的关联 牛皮癣患者。总而言之，该提案将展示一种新型机制 牛皮癣的发病机理并将肥胖相关的牛皮癣发育联系起来。因此，针对E-FABP可能会提供 牛皮癣和其他炎症性皮肤疾病的一种新型策略。