Plasmacytoid Dendritic Cells in Malignant Glioma

项目摘要/摘要 这份K08临床科学家导师研究职业发展奖提案描述了一个为期5年的 马华·戴伊博士的神经肿瘤学学术生涯发展培训计划。目前， 戴伊博士是印第安纳大学医学院神经外科的终身教职助理教授。 在芝加哥大学接受神经外科住院医师培训期间，她花了两年时间在她的一位同事那里 莱斯尼亚克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 神经胶质瘤。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 精通先进的免疫学研究技术，(2)掌握各种转基因小鼠的专业知识 模型和(3)熟练掌握先进的分子生物学技术和两个主要培训目标： (1)口头和书面介绍研究成果的培训，包括赠款准备和(2)开发 成功的学术生涯所必需的专业技能。 拟议的K08项目将在印第安纳大学神经外科进行 医学院。IUSM的这种充满活力的研究环境包括充足的免疫学机会 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 不断扩大的翻译神经肿瘤学研究人员群体。主要导师兰迪·布鲁特凯维奇博士是一位 世界著名的国立卫生研究院资助的肿瘤免疫学家和共同导师Maciej Lesniak博士，一位卓有成效的非常优秀的 受资助的神经外科医生和神经肿瘤学研究人员，他们都有超过10年的基础 免疫学和神经肿瘤学研究以及非常成功和成熟的指导记录 初级调查员。候选人还将受益于当地的指导委员会，这些委员会共同拥有 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有丰富的经验 生物学，以及NIH独立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确定免疫抑制的机制，使其成为靶向 免疫治疗在恶性胶质瘤的背景下无效。这将通过研究 中心假说下的两种免疫抑制细胞群：pDC和Tregs：MHC II受限 浆细胞样树突状细胞提呈抗原诱导Treg细胞增殖并参与脑胶质瘤的发生 免疫抑制。这个拟议项目的完成将实现两个重要目标：(1)解决 充分认识到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) 解决在理解中枢神经系统抗原呈递的作用和免疫治疗失败方面的关键差距。 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 申请者利用免疫学/分子发现建立独立研究人员的职业生涯 解决与临床相关的问题。 _

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. _