C5a receptor on mast cells in inflammatory arthritis

描述（由申请人提供）：炎性关节炎是国家卫生保健的主要重点，但滑膜炎的机制仍不完全清楚。使用与人类类风湿关节炎相似的小鼠系统，我们的实验室最近表明，肥大细胞是滑膜炎发生所必需的。然而，这些细胞在关节中被激活的机制，以及通过它们参与滑膜炎的效应作用，仍然不清楚。我们现在提供的数据表明，肥大细胞缺乏补体片段C5a （C5aR）的受体或缺乏IgG的Fc受体（Fc γ RIM），不能介导关节炎。在这些实验的基础上，候选人提出了一系列体外研究，以确定肥大细胞激活的途径，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。这些实验将促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，可能有助于确定人类炎症性关节炎治疗的新靶点。在儿科和成人风湿病学方面获得委员会认证，候选人寻求K08研究职业奖，以促进从医生到医生科学家的过渡。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计划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他的专业发展，走向科学独立。最终，候选人的目标是加入一个学术院系，以从事儿童关节炎发病机制的研究。

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.