P2X7R Signaling in Psoriasis Pathogenesis

银屑病发病机制中的 P2X7R 信号转导

• 批准号: 9302678
• 负责人: ALICIA R MATHERS
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302678
• 关键词: Acute; Address; Adverse effects; Affect; Agonist; Alpha Cell; Autoimmune Diseases; Benchmarking; Cells; Chronic; Chronic small plaque psoriasis; Comb animal structure; Complex; Cutaneous; Development; Disease; Effector Cell; Environment; Feedback; Future; Genetic Predisposition to Disease; Goals; Human; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-1 beta; Interleukin-15; Interleukin-17; Interleukin-6; Lead; Lesion; Link; Long-Term Effects; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Natural Immunity; Nature; Necrosis; Nuclear Translocation; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; Predisposition; Psoriasis; Reactive Oxygen Species; Receptor Signaling; Relapse; Role; Signal Pathway; Signal Transduction; Site; Skin; Stimulus; Stress; Testing; Th1 Cells; Therapeutic; Therapeutic Studies; Trauma; Xenograft Model; clinically relevant; combinatorial; cytokine; humanized mouse; innovation; interleukin-23; keratinocyte; knowledge base; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; pre-clinical; preclinical study; public health relevance; receptor; receptor expression; targeted treatment

 DESCRIPTION (provided by applicant): Psoriasis is a cutaneous autoimmune disease that affects as many as 125 million people worldwide. Current therapeutics for psoriasis include systemic acting immuno-suppressive drugs for which the long-term effects remain a concern. Psoriasis is a cell-mediated disease dependent on T helper (Th) 17 effector cells that are biased by cutaneous DCs. Importantly, the stimuli that induce DCs and keratinocytes to secrete Th polarizing cytokines, particularly in psoriasis, are complex and not completely understood. In this context, ATP is a particularly appealing alarmin that, via P2X7 receptor (P2X7R) signaling, induces NF-¿B activation and the IL- 23/IL-17 axis, both of which have been shown to be psoriasis susceptibility pathways. Thus, P2X7R signaling links early inflammatory triggers with psoriasis susceptibility factors. Interestingly, NF-¿B also leads to the maintenance of P2X7R expression forming a positive feedback mechanism. Results from our ongoing studies support a currently unappreciated role for P2X7R signaling in psoriasis pathogenesis. Specifically, we provide evidence that in healthy human skin, P2X7R signaling induces innate immunity, stimulates DCs to express IL- 1ß, IL-6, IL-23, IL-15, and VEGF, and promotes a Th17 bias. Additionally, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. This increased P2X7R expression in non-lesional skin represents a primary abnormality in the skin of patients with psoriasis, rather than a secondary effect of inflammation. Supported by this theoretical and experimental rationale, we hypothesize that within a genetically susceptible microenvironment cutaneous P2X7R signaling is a mechanism of psoriasis pathogenesis that can be a target for therapeutics. Thus, our goal in this preclinical proposal is to determine the involvement of P2X7R signaling in the development and maintenance of psoriatic lesions, and to elucidate novel P2X7R-dependent pathogenic mechanisms that can be exploited for novel psoriasis therapies. To test our novel and innovative hypothesis we have established the following specific aims: Aim 1 will define the inflammatory pathways induced by cutaneous P2X7R signaling. Aim 2 will establish the involvement of P2X7R signaling in psoriasis pathogenesis within a genetically susceptible microenvironment, and Aim 3 will examine the therapeutic capacity of P2X7R antagonist to diminish psoriatic lesions. The conserved nature of ATP and P2X7R signaling pathways in mice and humans supports the translational value of the studies we propose and provide an opportunity to utilize a unique and innovative approach by combing both human and murine models of psoriasis. At the conclusion of this proposal we will have determined that P2X7R signaling is pathogenic in genetically susceptible psoriatic microenvironments. Our results will lead to an increased scientific knowledge base, the development of a model to further examine P2X7R signaling mechanisms and psoriasis pathogenesis, and proof-of-principle studies for new therapeutic strategies for future proposals.

 描述（由申请人提供）：银屑病是一种皮肤自身免疫性疾病，影响全世界多达1.25亿人。目前银屑病的治疗方法包括全身作用的免疫抑制药物，其长期作用仍然是一个问题。银屑病是一种细胞介导的疾病，依赖于T辅助细胞（Th）17效应细胞，这些效应细胞受到皮肤DC的偏置。重要的是，刺激诱导DC和角质形成细胞分泌Th极化细胞因子，特别是在银屑病，是复杂的，并没有完全理解。在这种情况下，ATP是一种特别有吸引力的alarmin，通过P2 X7受体（P2 X7 R）信号传导，诱导NF-B激活和IL- 23/IL-17轴，这两者都已被证明是银屑病易感性途径。因此，P2 X7 R信号转导将早期炎症触发因子与银屑病易感因子联系起来。有趣的是，NF-B还导致P2 X7 R表达的维持，形成正反馈机制。我们正在进行的研究结果支持P2 X7 R信号在银屑病发病机制中的作用。具体而言，我们提供的证据表明，在健康的人皮肤中，P2 X7 R信号转导诱导先天免疫，刺激DC表达IL-1 β，IL-6，IL-23，IL-15和VEGF，并促进Th 17偏好。此外，与健康供体相比，P2 X7 R表达在银屑病患者的病变和非病变皮肤中增加。这种在非病变皮肤中P2 X7 R表达的增加代表了银屑病患者皮肤中的原发性异常，而不是炎症的继发性影响。在这一理论和实验原理的支持下，我们假设在遗传易感的微环境中，皮肤P2 X7 R信号传导是银屑病发病机制的一种机制，可以成为治疗的靶点。因此，我们在这项临床前提案中的目标是确定P2 X7 R信号传导在银屑病病变的发展和维持中的参与，并阐明可用于新型银屑病治疗的新型P2 X7 R依赖性致病机制。为了测试我们的新的和创新的假设，我们已经建立了以下具体目标：目标1将定义皮肤P2 X7 R信号传导诱导的炎症通路。目的2将在遗传易感的微环境中建立P2 X7 R信号转导在银屑病发病机制中的参与，目的3将检查P2 X7 R拮抗剂减少银屑病病变的治疗能力。ATP和P2 X7 R信号通路在小鼠和人类中的保守性支持了我们提出的研究的翻译价值，并提供了一个机会，通过结合人类和小鼠银屑病模型，利用独特的创新方法。在这个提议的结论中，我们将确定P2 X7 R信号传导在遗传易感的银屑病微环境中是致病的。我们的研究结果将导致增加科学知识基础，开发一个模型，以进一步研究P2 X7 R信号传导机制和银屑病发病机制，并为未来提出新的治疗策略进行原理验证研究。