Restriction of psoriatic skin and joint disease by A20

A20对银屑病皮肤和关节疾病的限制

• 批准号: 10536649
• 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
• 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/10536649
• 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; Epithelium; Evolution; Foundations; Functional disorder; Genes; Genetic Polymorphism; Genomics; Goals; Histologic; Human; Human Characteristics; IL17 gene; Immune; Immune signaling; Immunologist; Immunology; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Joints; Knock-in; Knowledge; Leadership; Learning; 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; Skin; Statistical Data Interpretation; T-Lymphocyte; TNF gene; Tissues; Tumor Necrosis Factor Receptor; Ubiquitin; United States; Variant; Zinc Fingers; arthropathies; career; career development; cytokine; early detection biomarkers; experimental study; fascinate; immune cell infiltrate; 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

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.

项目总结：银屑病皮肤和关节疾病之间的关系仍然是个谜。一个子集 的银屑病患者发展为关节炎，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（Tnfaip 3）是一种广泛表达的蛋白质，其限制 多个炎症信号通路，并与银屑病和银屑病性关节炎的遗传相关。 人类的关节炎然而，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 在小鼠中预防远端手指银肩病皮肤和关节疾病，其病理学需要TNF、IL 17 A和T细胞。 早期疾病围绕表皮;因此，我们产生了仅允许A20诱导缺失的小鼠。 在成年期的角质形成细胞中（A20 iEKO小鼠）。值得注意的是，这些小鼠也会出现类似的银屑病皮肤， 需要TNF、IL 17 A和T细胞的关节疾病。我的目标是确定A20 角质形成细胞的失调协调皮肤和关节疾病。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的作用- 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是关键的， 以及它们的解剖学作用部位。目的3关注A20在角质形成细胞中的细胞内在作用，其中I 计划了解A20限制体内炎症通路的机制， 分化，以及下游TNFR和IL 17 R。总之，这些研究将揭示角质形成细胞如何 协调导致银屑病皮肤和关节疾病的炎症过程。这与NIAMS有关 因为这些研究可能有助于解释人类银屑病与银屑病关节炎的联系， 用于早期或潜在关节炎疾病的新的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，研究炎症是如何在 位于上皮组织如皮肤内。上述研究将提供一个杰出的 他们的目标是了解皮肤调节障碍如何导致关节炎症。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 以流变学为重点的研究人员。我还计划发展上皮生物学的关键研究技能， 转录组学和统计分析。这些发展目标将通过沿着的教学课程来实现 参加系列研讨会、讲习班和会议。加上马博士的指导， 一位领先的分子免疫学家，以及来自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 作为一名物理学家兼科学家的研究生涯。