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 近三分之一的银屑病患者会出现银屑病关节炎；然而，预测哪些患者 会发展成关节炎仍然具有挑战性。此外，治疗方法在治疗皮肤方面更成功 与关节疾病相比。阐明牛皮癣中皮肤和关节疾病的相关机制可能 有助于更早识别有关节炎风险的患者，并可能揭示新的治疗策略。 Tnfaip3 (A20) 的多态性会降低其表达，与以下风险增加相关： 银屑病和银屑病关节炎。此外，与牛皮癣患者相比，A20 水平降低 给未受影响的个人。这些数据表明 A20 是银屑病炎症的重要限制因子； 然而，A20 预防银屑病的机制仍不清楚。 在我们之前的工作中，我们生成了 A20 的敲入小鼠突变体，该突变体自发发育 病理学类似于银屑病皮肤和关节病。这些小鼠中最早的组织学炎症 包围表皮，表明角质形成细胞的作用。因此，我们培育出能够 角质形成细胞中 A20 的诱导性缺失。值得注意的是，这些小鼠患上了银屑病皮肤和关节疾病 依赖于 TNF、IL23、IL17A 和 T 细胞，反映了介导人类银屑病疾病的已知因素。 为了确定由角质形成细胞 A20 丢失引发的最早的分子事件，我们进行了 RNASeq A20 缺失一周后的表皮。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 基因在人类银屑病斑块中强烈表达；然而，它们的诱导机制 它们在疾病发病机制中的作用尚不清楚。 在这里，我们提出旨在确定激活抗病毒基因的分子机制的研究 角质形成细胞 A20 丢失后的程序。我们将利用原代小鼠的体外培养系统 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。 我们还将确定体内观察到的抗病毒基因特征是否取决于 已知细胞因子在牛皮癣中发挥作用。总之，这些研究可能揭示抗病毒基因如何发挥作用 在人类牛皮癣中被激活并导致对其致病意义的了解。作为抗病毒药物 途径与目前的治疗目标不同，这可能会导致新的治疗策略 并揭示银屑病关节病临床前生物标志物的新机会。