Choline kinase: a novel target for rheumatoid arthritis

描述(由申请人提供)：本建议书描述了实验室和临床基础研究中的五年指导性研究计划，这对首席调查员作为独立调查员的发展至关重要。这位首席研究员已经完成了她在西班牙巴塞罗那的医学研究，专业是风湿病学，以及免疫学博士学位。然后她搬到圣地亚哥，加入迈克尔·卡林博士的实验室，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研究奖学金，并将通过一个有重点的个性化职业发展计划来扩大她的研究技能。该计划将提供用于慢性炎症和类风湿关节炎(RA)的滑膜成纤维细胞和关节炎模型的分子和细胞生物学方面的培训。到她的获奖期结束时，她还将发展出在风湿病领域进行临床前翻译研究和以患者为导向的研究所需的一整套技能。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，这些工具可以作为独立研究员应用于她的研究。加里·S·费尔斯坦博士是加州大学圣地亚哥分校的医学教授兼翻译研究所所长，他将指导首席研究员的科学发展。费尔斯坦博士是公认的 信号转导和类风湿关节炎的发病机制，并有很强的记录指导内科科学家。迈克尔·卡林博士也是公认的信号转导领域的领导者，炎症将作为这一领域的共同导师提供额外的指导。卡瓦诺博士作为一名临床导师，将利用患者样本协助开发新的生物标记物。值得注意的是，首席研究员在生物标记物分析、滑膜成纤维细胞生物学、以患者为中心的研究和临床试验方面没有经验，这些技能将是过渡到独立研究者所必需的。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记物。加州大学圣迭戈分校医学系的授课课程、研讨会、期刊俱乐部以及在支持性学术环境中进行实验室技术具体培训的80%受保护时间将补充培训计划。该研究建议将重点放在胆碱激酶在与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为治疗炎症性疾病的潜在治疗靶点。我们还将探索该激酶及其下游产物作为诊断或预后生物标记物的作用。这项建议建立在初步研究的基础上，该研究证实了胆碱激酶在类风湿关节炎患者成纤维样滑膜细胞的增殖和存活中的一种新功能。建议的研究将探索胆碱激酶在RA的关键信号事件、炎症和关节破坏中的功能和调节。此外，将在来自RA患者的细胞和组织样本中确定胆碱激酶的表达、功能和调节。将确定由临床疾病测量确定的胆碱激酶代谢产物模式和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