Restriction of psoriatic skin and joint disease by A20

A20对银屑病皮肤和关节疾病的限制

基本信息

批准号：
10343769
负责人：
Bahram Razani
金额：
$ 18.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343769
关键词：
3-Dimensional A20 protein Adult Advisory Committees Affect Anatomy Antigens Arthritis Automobile Driving Binding Binding Proteins Biology Cells Cellular Immunology Chronic small plaque psoriasis Complex Cutaneous Cytokine Network Pathway Data Defect Development Development Plans Diagnosis Digit structure Disease Distal Early Diagnosis Educational workshop Epidermis Epithelial Evolution Foundations Functional disorder Genes Genetic Polymorphism Genomics Goals Histologic Human Human Characteristics Immune Immune signaling Immunologist Immunology Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Interleukin-17 Joints Knock-in Knowledge Lead Leadership Learning Light Link Location Mentors Mentorship Modeling Molecular Mouse Strains Mus NF-kappa B National Institute of Arthritis and Musculoskeletal and Skin Diseases Nature Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phase Physicians Play Population Positioning Attribute Predisposition Process Protein Biochemistry Proteins Psoriasis Psoriatic Arthritis Publishing Research Research Personnel Rheumatology Role Scientist Series Signal Pathway Signal Transduction Signaling Protein Skin Statistical Data Interpretation T-Lymphocyte TNF gene Tissues Tumor Necrosis Factor Receptor Tumor-infiltrating immune cells Ubiquitin United States Variant Zinc Fingers arthropathies career career development cytokine early detection biomarkers experimental study fascinate improved in vivo joint destruction joint inflammation keratinocyte keratinocyte differentiation mouse model multidisciplinary mutant new therapeutic target novel novel therapeutic intervention novel therapeutics patient subsets prevent programs skills skin disorder symposium therapeutic biomarker transcriptomics two-dimensional

项目摘要

PROJECT SUMMARY: The relationship between psoriatic skin and joint disease remains enigmatic. A subset of patients with psoriasis develop arthritis, early diagnosis of which is challenging. Additionally, therapies for skin disease are less successful at treating arthritis. A20 (Tnfaip3) is a broadly-expressed protein that restricts multiple inflammatory signaling pathways and is genetically associated with both psoriasis and psoriatic arthritis in humans. However, the molecular and tissue-specific mechanisms by which A20 restricts psoriatic disease are unknown. Our preliminary data shows that A20's capacity for binding linear ubiquitin is critical for preventing distal digit psoriatic skin and joint disease in mice, with pathology requiring TNF, IL17A, and T-cells. Early disease surrounded the epidermis; therefore, we generated mice allowing inducible deletion of A20 only in keratinocytes in adulthood (A20iEKO mice). Remarkably, these mice also develop similar psoriatic skin and joint disease that requires TNF, IL17A, and T-cells. I aim to determine the immune mechanisms by which A20 dysregulation in keratinocytes orchestrates skin and joint disease. Aim 1 centers around understanding the cytokine requirements for coordinating the pathogenic immune infiltrate. In Aim 2 I will dissect the role of T- cells by determining which subsets or antigen-specific cells are critical for pathogenic cytokine secretion as well as their anatomical sites of action. Aim 3 focuses on the cell-intrinsic role of A20 in keratinocytes, where I plan to understand the mechanisms by which A20 restricts inflammatory pathways in vivo, during keratinocyte differentiation, and downstream TNFR and IL17R. Together, these studies will reveal how keratinocytes can orchestrate an inflammatory process that results in psoriatic skin and joint disease. This is relevant to NIAMS because these studies may help explain how human psoriasis is connected to psoriatic arthritis and may reveal novel therapeutic targets or biomarkers for early or potential arthritic disease. My long-term goal is to establish an independent research program studying how inflammation remains localized within epithelial tissues such as the skin. The studies described above will provide an outstanding starting point as they aim to understand how skin dysregulation can cause joint inflammation. My research background is primarily in cellular signaling and protein biochemistry. My career development aims are to build my intellectual and scientific foundation in cellular immunology and develop professional relationships with rheumatology-focused researchers. I also plan on developing key research skills in epithelial biology as well as transcriptomic and statistical analysis. These development goals will be pursued with didactic courses along with participation in seminar series, workshops, and conferences. Together with mentorship from Dr. Averil Ma, a leading molecular immunologist, and guidance from a multidisciplinary scientific advisory committee of immunologists, epithelial biologists, and genomics experts, these aims will position me for an independent research career as a physician-scientist.

项目摘要：银屑病皮肤与关节疾病之间的关系仍然是个谜。一个子集的牛皮癣患者会出现关节炎，其早期诊断具有挑战性。此外，治疗皮肤病在治疗关节炎方面不太成功。 A20 (Tnfaip3) 是一种广泛表达的蛋白质，限制多种炎症信号传导途径，并且与银屑病和银屑病有遗传相关性人类关节炎。然而，A20 限制银屑病的分子和组织特异性机制疾病未知。我们的初步数据表明，A20 结合线性泛素的能力对于预防小鼠远端手指银屑病皮肤和关节疾病，其病理学需要 TNF、IL17A 和 T 细胞。早期疾病围绕表皮；因此，我们培育了仅允许诱导性缺失 A20 的小鼠成年期角质形成细胞（A20iEKO 小鼠）。值得注意的是，这些小鼠也出现类似的银屑病皮肤和需要 TNF、IL17A 和 T 细胞的关节疾病。我的目标是确定 A20 的免疫机制角质形成细胞的失调会导致皮肤和关节疾病。目标 1 围绕理解协调致病性免疫浸润的细胞因子需求。在目标 2 中我将剖析 T 的角色- 通过确定哪些亚群或抗原特异性细胞对于致病性细胞因子分泌至关重要，以及它们的作用解剖部位。目标 3 重点关注 A20 在角质形成细胞中的细胞内在作用，其中我计划了解 A20 在角质形成细胞过程中限制体内炎症途径的机制分化，以及下游 TNFR 和 IL17R。这些研究将共同揭示角质形成细胞如何精心策划导致银屑病皮肤和关节疾病的炎症过程。这与 NIAMS 相关因为这些研究可能有助于解释人类牛皮癣与牛皮癣关节炎之间的关系，并可能揭示早期或潜在关节炎疾病的新治疗靶点或生物标志物。我的长期目标是建立一个独立的研究项目，研究炎症如何持续存在位于上皮组织内，例如皮肤。上述研究将提供出色的他们的目的是了解皮肤失调如何导致关节炎症。我的研究背景主要是细胞信号传导和蛋白质生物化学。我的职业发展目标是建立我在细胞免疫学方面的知识和科学基础，并与以风湿病学为重点的研究人员。我还计划发展上皮生物学以及转录组和统计分析。这些发展目标将通过教学课程来实现参加系列研讨会、讲习班和会议。在Averil Ma博士的指导下，领先的分子免疫学家，以及多学科科学咨询委员会的指导免疫学家、上皮生物学家和基因组学专家，这些目标将使我成为一个独立的作为一名医师科学家的研究生涯。