Choline kinase: a novel target for rheumatoid arthritis

描述（由申请人提供）：本提案描述了一项为期五年的实验室和临床研究指导研究计划，该计划对主要研究者作为独立研究者的发展至关重要。主要研究者已完成医学研究，专攻流变学，并获得博士学位。在西班牙巴塞罗那学习免疫学。然后，她搬到圣地亚哥加入迈克尔·卡琳博士的实验室，接受信号转导的博士后培训。她现在正在实现在圣地亚哥的加州大学的流变学奖学金，并将通过一个集中的个性化的职业发展计划扩大她的研究技能。该计划将提供滑膜成纤维细胞和关节炎模型的分子和细胞生物学培训，用于慢性炎症和类风湿性关节炎（RA）。在她的获奖期间结束时，她还将开发所需的技能集进行临床前转化研究的独立调查，并在流变学领域以患者为导向的研究。她的研究还需要在蛋白质组学，NMR和代谢组学方面进行额外的培训，这将为她提供重要的新工具，可以作为独立研究者应用于她的研究。加里博士S. Firestein是加州大学圣地亚哥分校的医学教授和转化研究院院长，他将指导首席研究员的科学发展。Firestein博士是公认的领导者， 信号转导和类风湿性关节炎的发病机制，并有指导医生科学家的良好记录。Michael Karin博士也是信号转导和炎症领域公认的领导者，他将作为该领域的共同导师提供额外的指导。Kavanaugh博士作为临床导师，将协助使用患者样本开发新的生物标志物。值得注意的是，主要研究者在生物标志物分析滑膜成纤维细胞生物学、以患者为导向的研究和临床试验方面没有经验，这些技能对于过渡到独立研究者至关重要。此外，我们的合作者将帮助使用代谢组学研究的技术和信息学，解释结果以及如何将其应用于开发新的生物标志物。教学课程，研讨会，期刊俱乐部和80%的保护时间在UCSD医学系的支持性学术环境中进行实验室技术的具体培训将补充培训计划。该研究计划将重点关注胆碱激酶在与RA相关的慢性炎症和关节破坏中的作用。此外，这些研究将确定这种酶是否是治疗炎症性疾病的潜在治疗靶点。我们还将探讨这种激酶及其下游产物作为诊断或预后生物标志物的作用。该建议建立在初步研究的基础上，初步研究表明胆碱激酶在RA患者成纤维细胞样滑膜细胞增殖和存活中的新功能。拟开展的研究将探讨胆碱激酶在RA关键信号事件、炎症和关节破坏中的功能和调节。此外，胆碱激酶的表达、功能和调节将在来自RA患者的细胞和组织样品中确定。将确定胆碱激酶代谢物模式与通过临床疾病测量确定的疾病活动性之间的关系

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