PAD2: An Arginine Deiminase that Regulates Arthritis

描述（由申请人提供）：类风湿性关节炎（RA）是一种常见的慢性滑膜关节炎性疾病。瓜氨酸翻译后修饰是通过肽基精氨酸脱亚胺酶（PAD）家族成员将肽基精氨酸残基转化为瓜氨酸氨基酸而形成的。PAD酶与RA病理学有关，因为许多RA自身抗体针对瓜氨酸化蛋白。类风湿性关节炎中瓜氨酸化表位自身抗体的发展表明异常的PAD活性有助于疾病的发生。PAD 2表达与RA滑膜组织中的炎症密切相关。有趣的是，PAD 2 KO小鼠在炎性关节炎的血清转移模型中表现出疾病改善。肥大细胞有助于炎症性关节炎的实验模型中的疾病发病机制，我们已经确定肥大细胞作为PAD 2酶的主要来源。我们发现，炎症“危险”信号ATP对P2 X7受体的激活以PAD 2依赖性方式诱导了强有力的瓜氨酸蛋白。待评估的总体假设是，炎症“危险”信号激活肥大细胞衍生的PAD 2会导致炎症性关节炎。具体目标：该建议的具体目的是描绘肥大细胞中的P2 X7 R/PAD 2通路，并确定肥大细胞衍生的PAD 2对炎性关节炎的贡献。重要性：这些研究将提供RA中PAD 2激活机制的见解，并将支持我们的长期目标，即在了解RA发病机制的基础上开发预防和治疗RA的方法。 公共卫生相关性：风湿性关节炎（RA）是一种慢性炎症性自身免疫性疾病，影响世界人口的2%。肽基精氨酸脱亚胺酶（PAD）催化蛋白质瓜氨酸，并通过遗传多态性和识别瓜氨酸修饰的抗体的存在与RA相关。这项研究计划的目的是了解一种特定的酶PAD 2如何促进炎症性关节炎。

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.