PAD2: An Arginine Deiminase that Regulates Arthritis

PAD2：一种调节关节炎的精氨酸脱亚氨酶

• 批准号: 8523780
• 负责人: KERRI A MOWEN
• 金额: $ 22.27万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/8523780
• 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

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.

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症性疾病。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 病理有关，因为许多 RA 自身抗体针对瓜氨酸蛋白。 RA 中针对瓜氨酸表位的自身抗体的产生表明异常的 PAD 活性会导致疾病。 PAD2 表达与 RA 滑膜组织炎症密切相关。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疾病的改善。肥大细胞在炎症性关节炎实验模型中参与疾病发病机制，我们已确定肥大细胞是 PAD2 酶的主要来源。我们发现，炎症“危险”信号 ATP 激活 P2X7 受体会以 PAD2 依赖性方式诱导强大的蛋白质瓜氨酸化。待评估的总体假设是，炎症“危险”信号激活肥大细胞衍生的 PAD2 会导致炎症性关节炎。具体目标：该提案的具体目标是描绘肥大细胞中的 P2X7R/PAD2 通路，并确定肥大细胞衍生的 PAD2 对炎症性关节炎的贡献。意义：这些研究将深入了解 RA 中 PAD2 激活的机制，并将支持我们在了解 RA 发病机制的分子机制的基础上开发预防和治疗 RA 方法的长期目标。

项目成果

Citrullination regulates pluripotency and histone H1 binding to chromatin.

• DOI: 10.1038/nature12942
• 发表时间: 2014-03-06
• 期刊: Nature
• 影响因子: 64.8
• 作者: Christophorou MA;Castelo-Branco G;Halley-Stott RP;Oliveira CS;Loos R;Radzisheuskaya A;Mowen KA;Bertone P;Silva JC;Zernicka-Goetz M;Nielsen ML;Gurdon JB;Kouzarides T
• 通讯作者: Kouzarides T