Plasmacytoid Dendritic Cells in Malignant Glioma

项目总结/摘要 K08指导临床科学家研究职业发展奖提案描述了一个为期5年的 为Mahua Dey博士提供神经肿瘤学学术生涯发展的培训计划。目前， 博士戴伊是印第安纳州大学医学院神经外科终身助理教授。 在芝加哥大学的神经外科住院医师培训期间，她在一个合作机构工作了两年， Lesniak博士的神经肿瘤学实验室研究浆细胞样树突状细胞在恶性肿瘤中的作用， 胶质瘤为了实现完全的研究独立，她确定了三个关键的研究目标：（1）获得 熟练掌握先进的免疫学研究技术，（2）获得各种转基因小鼠的专业知识 模型和（3）获得先进的分子生物学技术和两个关键培训目标的熟练程度： (1)培训口头和书面陈述研究成果，包括拨款准备和（2）发展 成功的学术生涯所必需的专业技能。 拟议的K08项目将在印第安纳州大学神经外科系进行 医学院。IUSM充满活力的研究环境包括充分的免疫学研究 核心设施，组织学，DNA核心设施，显微镜资源和动物住房，它培养了一个 扩大转化神经肿瘤学研究人员的群体。主要导师，兰迪Brutkiewicz博士， 世界著名的NIH资助的肿瘤免疫学家和共同导师Maciej Lesniak博士，一个富有成效的，非常好的 基金神经外科医生和神经肿瘤学研究人员，都有超过10年的经验，基本 免疫学和神经肿瘤学研究以及非常成功和建立的指导记录 初级调查员候选人还将受益于当地的指导委员会， 在免疫学、神经肿瘤学、各种转基因小鼠模型以及分子生物学方面具有丰富的经验， 生物学，以及独立NIH资助和培训年轻研究人员的良好记录。 该研究项目的重点是定义免疫抑制机制，使靶向 免疫疗法在恶性胶质瘤的情况下无效。这将通过研究以下方面的作用来实现： 两个免疫抑制细胞群：pDC和TcB，在中心假设下：MHC II限制性 浆细胞样树突状细胞的抗原提呈诱导Treg细胞增殖并促进胶质瘤 免疫抑制本项目的完成将实现两个重要目标：（1）解决 参与转化研究的训练有素的临床科学家的严重短缺，以及（2） 解决在理解CNS抗原呈递和免疫治疗失败的作用方面的关键差距。 因此，拟议的计划将提供培训和初步数据，以支持R01应用，并允许 申请人作为一名独立的研究人员，利用免疫学/分子发现， 解决临床相关问题。 _

PROJECT SUMMARY/ABSTRACT This K08 Mentored Clinical Scientist Research Career Development Award proposal describes a 5-year training program for the development of an academic career in neuro-oncology for Dr. Mahua Dey. At present, Dr. Dey is a Tenure Track Assistant Professor of Neurosurgery at Indiana University School of Medicine. During her neurosurgery residency training at University of Chicago she spent two years in one of her co- mentor, Dr. Lesniak's neuro-oncology laboratory studying the role of plasmacytoid dendritic cells in malignant glioma. To achieve full research independence, she has identified three key research objectives: (1) To gain proficiency in advanced immunological research techniques, (2) To gain expertise in various transgenic mouse models and (3) To gain proficiency in advanced molecular biology techniques and two key training objectives: (1) Train in oral and written presentation of research findings, including grant preparation and (2) Develop professional skills necessary for a successful academic career. The proposed K08 project will take place in the Department of Neurosurgery at the Indiana University School of Medicine. This vigorous research environment at the IUSM includes ample access to immunology core facility, histology, DNA core facility, microscopy resources and animal housing, and it nurtures an expanding group of translational neuro-oncology researchers. The primary mentor, Dr. Randy Brutkiewicz, a world renound NIH funded tumor immunologist and co-mentor, Dr. Maciej Lesniak, a productive and very well funded neurosurgeon and neuro-oncology researcher, both have more than 10 years of experience with basic immunology and neuro-oncology research and a very successful and established track record of mentoring junior investigators. The candidate will also benefit from the local mentoring committee that collectively have extensive experience in immunology, neuro-oncology, various transgenic mouse models as well as molecular biology, and a strong track record of independent NIH funding and training young investigators. The research project focuses on defining the mechanisms of immunosuppression that renders targeted immunotherapy ineffective in the setting of malignant glioma. This will be accomplished by studying the role of two immunosuppressive cell population: pDCs and Tregs under the central hypothesis: MHC II restricted antigen presentation by plasmacytoid dendritic cells induce Treg cells proliferation and contribute to glioma immunosuppression. The completion of this proposed project will accomplish two important goals: (1) address the well identified critical shortage of well-trained clinician scientists involved in translational research, and (2) address the critical gap in understanding the role of CNS antigen presentation and failure of immunotherapy. As a result the proposed plan will provide training and preliminary data to support an R01 application and allow the applicant to establish a career as an independent researcher using immunological/molecular discovery to address clinically relevant problems. _