PAD2: An Arginine Deiminase that Regulates Arthritis

PAD2：一种调节关节炎的精氨酸脱亚氨酶

基本信息

批准号：
8282488
负责人：
KERRI A MOWEN
金额：
$ 28.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282488
关键词：
Affect American Amino Acids Animals Anti-citrullinated peptide antibody Antibodies Applications Grants Arginine Arginine deiminase Arthritis Attenuated Autoantibodies Autoimmune Diseases Biological Markers Biopsy Specimen Cell Culture Techniques Chromosomes, Human, Pair 4 Chronic Citrulline Deposition Development Diagnostic Disease Disease Marker Disease Resistance Enzyme-Linked Immunosorbent Assay Enzymes Epitopes Ethnic group European Exhibits Experimental Models Family member Gene Expression Genes Genetic Polymorphism Goals Human Immunoblot Analysis Inflammation Inflammatory Inflammatory Response Japanese Population Joints Koreans Link Manuscripts Methods Modeling Modification Molecular Mus Pathogenesis Pathology Pathway interactions Patients Phase Phenotype Plasma Play Population Post-Translational Protein Processing Preparation Prevalence Prevention Process Protein-arginine deiminase Proteins Reaction Research Proposals Resistance Rheumatoid Arthritis Sensitivity and Specificity Serum Severities Severity of illness Signal Transduction Source Testing Therapeutic Tissues Variant Wild Type Mouse base cell type cohort genome wide association study insight macrophage mast cell neutrophil new therapeutic target novel therapeutics programs receptor reconstitution research study response

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a frequent and chronic inflammatory disease of the synovial joints. The citrulline posttranslational modification is forme by the conversion of peptidylarginine residues into the citrulline amino acid by peptidylarginine deiminase (PAD) family members. PAD enzymes have been implicated in RA pathology because many RA autoantibodies are directed against citrullinated proteins. The development of autoantibodies to citrullinated epitopes in RA suggests that aberrant PAD activity contributes disease. PAD2 expression is closely linked with inflammation in RA synovial tissue. Interestingly, PAD2 KO mice exhibit ameliorated disease in a serum-transfer model of inflammatory arthritis. Mast cells contribute to disease pathogenesis in experimental models of inflammatory arthritis, and we have identified mast cells as a major source of the PAD2 enzyme. We find that activation of the P2X7 receptor by the inflammatory "danger" signal ATP induces robust protein citrullination in a PAD2-dependent manner. The overall HYPOTHESIS to be evaluated is that activation of mast cell-derived PAD2 by an inflammatory "danger" signal contributes to inflammatory arthritis. Specific aims: The specific aims of this proposal are to delineate the P2X7R/PAD2 pathway in mast cells and to determine the contribution of mast cell derived PAD2 to inflammatory arthritis. Significance: These studies will provide insight the mechanism of PAD2 activation in RA and will support our long-term goal to develop methods for the prevention and treatment of RA based on understanding the molecular mechanisms underlying RA pathogenesis. PUBLIC HEALTH RELEVANCE: Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease that affects up to 2% of the world population. Peptidylarginine deiminase (PAD) enzymes catalyze protein citrullination and have been linked to RA through genetic polymorphisms and the presence of antibodies recognizing the citrulline modification. The goal of this research proposal is to understand how a specific enzyme, PAD2, promotes inflammatory arthritis.

描述（由申请人提供）：类风湿关节炎（RA）是滑膜关节的常见慢性炎症性疾病。瓜氨酸后翻译后修饰是通过肽基金蛋白脱氨酸酶（PAD）家族成员将肽基金蛋白残基转化为瓜氨酸的形成。 PAD酶已经与RA病理学有关，因为许多RA自身抗体针对柠檬酸蛋白。在RA中，自身抗体的发育表明，异常的PAD活性会导致疾病。 PAD2表达与RA滑膜组织中的炎症密切相关。有趣的是，PAD2 KO小鼠在炎症性关节炎的血清转移模型中表现出改善疾病。肥大细胞在炎症性关节炎的实验模型中有助于疾病发病机理，我们将肥大细胞确定为PAD2酶的主要来源。我们发现，通过炎症“危险”信号ATP激活P2X7受体会以PAD2依赖性方式诱导稳健的蛋白质柠檬酸化。要评估的总体假设是，通过炎症“危险”信号激活了肥大细胞衍生的PAD2，这会导致炎症性关节炎。具体目的：该提案的具体目的是描绘肥大细胞中的P2X7R/PAD2途径，并确定跨肥大细胞衍生的PAD2对炎症性关节炎的贡献。意义：这些研究将为RA中PAD2激活的机制提供洞察力，并将支持我们基于理解RA发病机理的分子机制来开发预防和治疗RA的方法的长期目标。公共卫生相关性：类风湿关节炎（RA）是一种慢性炎症自身免疫性疾病，影响多达2％的世界人口。肽基金氨酸脱节酶（PAD）酶催化蛋白质柠檬酸硫磺化，并通过遗传多态性和识别cistrulline修饰的抗体的存在与RA有关。该研究建议的目的是了解特定酶PAD2如何促进炎症性关节炎。