C5a receptor on mast cells in inflammatory arthritis

炎症性关节炎肥大细胞上的 C5a 受体

• 批准号: 7261391
• 负责人: Peter A Nigrovic
• 金额: $ 12.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-14 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261391
• 关键词: Adult; Affinity; Animals; Arthritis; Autoantibodies; Autoimmune Process; Award; Biology; C5a anaphylatoxin receptor; Cells; Childhood; Complement; Complement 5a; Complement Receptor; Data; Development; Disease; Engraftment; Faculty; Fc Receptor; Gene Expression; Genetic Transcription; Genetic Translation; Goals; Health; Healthcare; Human; IgG Receptors; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Instruction; Interleukin-1; Joints; K/BxN model; Laboratories; Ligation; Link; Mediating; Mediator of activation protein; Mentors; Messenger RNA; Mus; Oligonucleotide Microarrays; Pathogenesis; Pathway interactions; Physicians; Production; Protein Biosynthesis; Research; Research Personnel; Rheumatoid Arthritis; Rheumatology; Role; Scientist; Screening procedure; Series; Serum; Surface; Synovial Membrane; Synovitis; System; TLR2 gene; Technical Expertise; Toll-Like Receptor 1; Training; Work; arthropathies; career; human disease; in vivo; mRNA Stability; mast cell; member; novel; programs; receptor; receptor expression; reconstitution; research study; response; secretion process; skills

DESCRIPTION (provided by applicant): Inflammatory arthritis is a major national health care priority, yet the mechanisms of synovitis remain incompletely understood. Using a murine system with similarities to human rheumatoid arthritis, our laboratory has recently shown that mast cells are required for the genesis of synovitis. However, the mechanisms by which these cells become activated in the joint, and the effecter functions through they participate in synnovitis, remain obscure. We now present data demonstrating that mast cells deficient in the receptor for the complement fragment C5a (C5aR) or in Fc receptors for IgG (Fc gamma RIM) are incapable of mediating arthritis. Extending these experiments, the candidate proposes a series of in vitro studies to define pathways of mast cell activation and identify candidate mediators through which mast cells could promote inflammatory joint disease. Informed by these results, targeted in vivo experiments will explore the importance of selected pathways and mediators in murine arthritis. These experiments will advance our understanding of the basic biology of the mast cell and help to clarify the intriguing role of mast cells in synovitis, potentially assisting in the identification of novel targets of therapy in human inflammatory arthritis. Board certified in both pediatric and adult rheumatology, the candidate seeks the K08 Research Career Award to facilitate a transition from physician to physician-scientist. The research will be conducted under the coordinated guidance of Dr. Michael B. Brenner, a senior investigator with an established training record, and Dr. David M. Lee, a junior faculty member with an active research program and technical expertise at the bench. Through the skill of these mentors, as well as a rigorous program of formal instruction, the candidate aims to continue his professional development toward scientific independence. Ultimately, the candidate's goal is to join an academic faculty in order to pursue research focused on the pathogenesis of arthritis in childhood.

描述（由申请人提供）：炎症性关节炎是国家医疗保健的一个主要优先事项，但滑膜炎的机制仍未完全了解。我们的实验室最近利用与人类类风湿性关节炎相似的小鼠系统表明，滑膜炎的发生需要肥大细胞。然而，这些细胞在关节中被激活的机制以及它们参与滑膜炎的效应器功能仍然不清楚。我们现在提供的数据表明，缺乏补体片段 C5a 受体 (C5aR) 或 IgG Fc 受体 (Fc gamma RIM) 的肥大细胞不能介导关节炎。扩展这些实验，候选人提出了一系列体外研究来定义肥大细胞激活途径并确定肥大细胞促进炎症性关节疾病的候选介质。根据这些结果，有针对性的体内实验将探索选定的途径和介质在小鼠关节炎中的重要性。这些实验将增进我们对肥大细胞基本生物学的理解，并有助于阐明肥大细胞在滑膜炎中的有趣作用，可能有助于识别人类炎症性关节炎的新治疗靶点。该候选人获得儿科和成人风湿病学委员会认证，寻求 K08 研究职业奖，以促进从医生到医生科学家的转变。该研究将在具有既定培训记录的高级研究员 Michael B. Brenner 博士和具有活跃研究项目和技术专长的初级教员 David M. Lee 博士的协调指导下进行。通过这些导师的技能以及严格的正式指导计划，候选人的目标是继续其专业发展，实现科学独立。最终，候选人的目标是加入学术团队，从事儿童关节炎发病机制的研究。