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: 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
• 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

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