Choline kinase: a novel target for rheumatoid arthritis

描述（由申请人提供）：该提案描述了一个为期五年的实验室和临床研究指导计划，这对主要研究者作为独立研究者的发展至关重要。首席研究员在西班牙巴塞罗那完成了她的医学研究，专攻风湿病学，并获得免疫学博士学位。随后，她搬到了圣地亚哥，加入迈克尔·卡琳博士的实验室，接受信号转导方面的博士后培训。她现在正在加州大学圣地亚哥分校获得风湿病学奖学金，并将通过专注的个性化职业发展计划扩展她的研究技能。该项目将提供滑膜成纤维细胞分子和细胞生物学方面的培训，以及用于慢性炎症和类风湿性关节炎（RA）的关节炎模型。在她的奖励期结束时，她还将发展在风湿病学领域进行临床前转化研究和以患者为导向的研究所需的独立调查的技能。她的研究还需要额外的蛋白质组学、核磁共振和代谢组学方面的培训，这将为她提供重要的新工具，可以应用于她作为独立研究者的研究。Gary S. Firestein博士是加州大学圣地亚哥分校转化研究所的医学教授和院长，他将指导首席研究员的科学发展。费尔斯坦博士是公认的

DESCRIPTION (provided by applicant): This proposal describes a five year mentored research program in laboratory and clinical based research essential to the development of the principal investigator as an independent investigator. The principal investigator has completed her medical studies, specializing in Rheumatology, and Ph.D. studies in Immunology in Barcelona, Spain. She then moved to San Diego to join Dr. Michael Karin's lab for her postdoctoral training in signal transduction. She is now realizing Rheumatology Fellowship at the University of California at San Diego and will expand upon her research skills through a focused individualized career development plan. The program will provide training in molecular and cell biology of synovial fibroblasts and arthritis models applied to chronic inflammation and rheumatoid arthritis (RA). By the end of her award period, she will also have developed the skill sets required to conduct independent investigation in pre-clinical translational research, and patient-oriented research in the field of Rheumatology. Her studies will also require additional training in proteomics, NMR, and metabolomics that will provide her with important new tools that can be applied to her research as an independent investigator. Dr. Gary S. Firestein is a professor of medicine and dean of translational research institute at UC San Diego and will mentor the principal investigator's scientific development. Dr. Firestein is a recognized leader in signal transduction and pathogenesis of rheumatoid arthritis and has a strong record of mentoring physician scientists. Dr. Michael Karin is also a recognized leader in signal transduction and inflammation will provide additional guidance as a co-mentor in this filed. Dr. Kavanaugh, as a clinical mentor, will assist with developing novel biomarkers using patient samples. Of note, the principal investigator has no experience in biomarker analysis synovial fibroblast biology, patient-oriented research, and clinical trials and those skills would be essential for transition to an independent investigator. In addition, our collaborators will help wth the use of the technology and informatics for metabolomics studies, with the interpretation of results and how it can be applied to developing new biomarkers. Didactic courses, seminars, journal clubs and 80% protected time for specific training in laboratory techniques in a supportive academic environment in the Department of Medicine at UCSD will complement the training program. The research proposal will focus on the role of choline kinase in chronic inflammation and joint destruction associated with RA. In addition, these studies will determine whether this enzyme is a potential therapeutic target to treat inflammatory disorders. We will also explore the role of this kinase and its downstream products as diagnostic or prognostic biomarker. The proposal builds upon preliminary studies demonstrating a novel function of choline kinase in proliferation and survival of fibroblast-like synoviocytes derived from RA patients. The proposed studies will explore function and regulation of choline kinase in key signaling events, inflammation and joint destruction in RA. In addition, expression, function and regulation of choline kinase will be determined in cells and tissue samples derived from patients with RA. The relationship between the choline kinase metabolites pattern and disease activity as determined by clinical disease measures will be determined