Role of antiviral signaling in psoriatic pathogenesis

抗病毒信号在银屑病发病机制中的作用

• 批准号: 10643178
• 负责人: Bahram Razani
• 金额: $ 16.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643178
• 关键词: A20 protein; Address; Adult; Animals; Antibodies; Arthritis; Biological Markers; Cells; Chronic small plaque psoriasis; Clinical; Cutaneous; Cytoprotection; Data; Development; Disease; Ear; Epidermis; Event; Gene Expression; Genes; Genetic Polymorphism; Grant; Histologic; Human; Human Genetics; IL17 gene; In Vitro; Individual; Inflammation; Interferon Receptor; Interferons; Joints; Knock-in Mouse; Knockout Mice; Learning; Link; Mediating; Methods; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Nature; Nucleic Acids; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Pilot Projects; Psoriasis; Psoriatic Arthritis; Research Personnel; Risk; Role; Signal Transduction; Skin; System; T-Lymphocyte; TNF gene; Therapeutic; Time; Viral; Viral Genes; Virulence Factors; Work; arthropathies; cytokine; disorder risk; gene induction; genetic signature; in vivo; keratinocyte; molecular marker; mouse model; novel; novel therapeutic intervention; pre-clinical; prevent; programs; receptor; risk variant; skin disorder; targeted treatment; transcriptome sequencing; treatment strategy

PROJECT ABSTRACT Nearly a third of patients with psoriasis develop psoriatic arthritis; however, predicting which patients will develop arthritis remains challenging. Additionally, therapeutics are more successful in treating skin compared to joint disease. Clarifying the mechanisms which connect skin and joint disease in psoriasis may help identify patients at risk for arthritis earlier and may reveal novel therapeutic strategies. Polymorphisms in Tnfaip3 (A20), which reduce its expression, are associated with increased risk of both psoriasis and psoriatic arthritis. Furthermore, patients with psoriasis display reduced A20 levels compared to unaffected individuals. These data suggest that A20 is an important restrictor of psoriatic inflammation; however, the mechanisms by which A20 prevents psoriatic disease remain unknown. In our prior work, we generated a knock-in mouse mutant of A20 that developed spontaneous pathology analogous to psoriatic skin and joint disease. The earliest histological inflammation in these mice surrounded the epidermis, suggesting a role for keratinocytes. Therefore, we generated mice capable of inducible deletion of A20 in keratinocytes. Remarkably, these mice developed psoriatic skin and joint disease dependent on TNF, IL23, IL17A, and T-cells, reflecting known factors that mediate human psoriatic disease. To identify the earliest molecular events initiated by keratinocyte A20 loss, we performed RNASeq of epidermis one week after A20 deletion. Surprisingly, we found profound induction of antiviral genes. Antiviral genes are strongly expressed in human psoriatic plaques; however, the mechanism by which they are induced and their role in disease pathogenesis is unknown. Here we propose studies aimed at identifying the molecular mechanisms which activate antiviral gene programs following loss of keratinocyte A20. We will utilize in vitro culture systems of primary murine keratinocytes combined with strategies to inhibit specific interferon receptors and viral nucleic acid receptors. We will also determine whether the antiviral gene signature observed in vivo depends on the presence of cytokines known to play a role in psoriasis. Together, these studies may shed light on how antiviral genes are activated in human psoriasis and lead to an understanding of their pathogenic significance. As antiviral pathways are distinct from those currently targeted therapeutically, this may lead to novel treatment strategies and reveal new opportunities for pre-clinical biomarkers of psoriatic joint disease.

项目摘要 牛皮癣患者中有将近三分之一患有牛皮癣关节炎。但是，预测哪些患者 会发育关节炎仍然具有挑战性。此外，治疗方法在治疗皮肤方面更为成功 与关节疾病相比。阐明连接牛皮癣皮肤和关节疾病的机制可能 帮助鉴定早些时候患有关节炎风险的患者，并可能揭示新的治疗策略。 TNFAIP3（A20）中降低表达的多态性与增加的风险有关 牛皮癣和银屑病关节炎。此外，牛皮癣患者的A20水平降低 给不受影响的人。这些数据表明A20是银屑病炎症的重要限制因子。 但是，A20阻止银屑病疾病的机制仍然未知。 在先前的工作中，我们生成了一个自发性的A20的敲入小鼠突变体 病理类似于银屑病皮肤和关节疾病。这些小鼠最早的组织学炎症 包围表皮，表明角质形成细胞的作用。因此，我们产生了能够 在角质形成细胞中A20的诱导缺失。值得注意的是，这些小鼠出现了银屑病皮肤和关节疾病 取决于TNF，IL23，IL17A和T细胞，反映了介导人类银屑病疾病的已知因素。 为了确定角质细胞A20损失发起的最早的分子事件，我们进行了RNASEQ A20删除一周后表皮。令人惊讶的是，我们发现了抗病毒基因的深刻诱导。抗病毒物质 基因在人的银屑病斑块中强烈表达；但是，它们诱导的机制 它们在疾病发病机理中的作用尚不清楚。 在这里，我们提出的研究旨在鉴定激活抗病毒基因的分子机制 失去角质形成细胞A20之后的程序。我们将利用主要鼠的体外培养系统 角质形成细胞结合抑制特定干扰素受体和病毒核酸受体的策略。 我们还将确定在体内观察到的抗病毒基因信号是否取决于 已知的细胞因子在牛皮癣中发挥作用。总之，这些研究可能会阐明抗病毒基因的方式 在人牛皮癣中被激活，导致对其致病意义的理解。作为抗病毒 途径与当前针对治疗的途径不同，这可能导致新的治疗策略 并揭示了银屑病联合疾病的临床前生物标志物的新机会。