Antigen specific modeling of glioma immunotherapy

描述(由申请人提供)：本提案旨在为安德鲁·T·帕尔萨博士提供在五年内发展成为一名学术内科医生和基础科学家的机会。帕尔萨博士是加州大学旧金山分校神经外科的助理教授，对脑瘤有临床和科学兴趣。他是一名执业神经外科医生，他将把50%-60%的学术努力投入到他的导师阿布·阿巴斯博士监督的科学培训项目中。帕尔萨博士的科学发展将通过研究生课程、研究研讨会和假设驱动的研究项目来促进，帕尔萨博士将作为主要研究员负责该项目。该项目名为“胶质瘤免疫治疗的抗原特异性建模”，解决了有关中枢神经系统免疫的基本问题。拟议的实验旨在检验局部抗肿瘤免疫与颅内神经胶质瘤负荷负相关的假设。神经胶质细胞在维持神经系统的功能完整性方面起着不可或缺的作用。当神经胶质细胞等神经元外细胞转化为恶性肿瘤时，可能会导致神经疾病。免疫治疗是传统辅助治疗的一种有吸引力的选择，因为它可以特异性地靶向恶性胶质细胞，同时保留包括神经元在内的周围细胞的功能。在抗原特异性胶质瘤转基因模型的背景下，将追求以下特定目标：1)确定T细胞对颅内胶质瘤特异性抗原的反应的动力学、部位和大小；2)分析肿瘤特异性抗原外周刺激后T细胞在中枢神经系统中的积聚；3)表征T细胞在转运到中枢神经系统后对肿瘤特异性抗原的反应。实现这些目标将有助于对抗原特异性免疫介导的抗中枢神经系统肿瘤作用的深入了解。重要的是，这些目标将使研究人员能够调整和测试一种模型，该模型概括了自发产生的神经胶质瘤的人类状况。这些目标的重点性质，结合加州大学旧金山分校的临床和科学环境，将为PI提供宝贵的培训经验。这项提议的长期目标是促进帕尔萨博士发展成为一名能够做出有意义科学贡献的独立研究员。

DESCRIPTION (provided by applicant): This proposal is designed to provide Dr. Andrew T. Parsa with the opportunity to develop as an academic physician and basic scientist over five years. Dr. Parsa is an Assistant Professor in the Department of Neurological Surgery at UCSF with a clinical and scientific interest in brain tumors. He is a practicing neurosurgeon who will be spending 50-60% of his academic efforts in a program of scientific training supervised by Dr. Abul Abbas, his mentor. The scientific development of Dr. Parsa will be facilitated by graduate coursework, research seminars, and a hypothesis driven research project for which Dr. Parsa will be primarily responsible as principal investigator. The project, entitled "Antigen Specific Modeling of Glioma Immunotherapy", addresses fundamental questions about immunity in the CNS. The proposed experiments are designed to test the hypothesis that local anti-tumor immunity inversely correlates with intracranial glial tumor burden. Glial cells are integrally involved in maintaining functional integrity of the nervous system. Neurological disorders can result when extra-neuronal cells such as glia transform into malignant tumors. Immunotherapy is an attractive alternative to conventional adjuvant therapy because it can specifically target malignant glial cells while preserving function of surrounding cells, including neurons. Within the context of a transgenic model of antigen specific glioma the following Specific Aims will be pursued to: 1) define the kinetics, sites and magnitude of T cell responses to intracranial glial tumor specific antigen, 2) analyze T cell accrual in the CNS after peripheral stimulation with tumor specific antigen, and 3) characterize T-cell responses against tumor specific antigen after trafficking to the CNS. Achieving these Aims will facilitate a refined understanding of antigen specific immune mediated effects against tumors of the CNS. Importantly, these Aims will allow the investigators to adapt and test a model that recapitulates the human condition of a spontaneously arising glial tumor. The focused nature of these Aims, combined with clinical and scientific environment at UCSF, will provide the PI with a valuable training experience. The long-term goal of this proposal is to facilitate the development of Dr. Parsa into an independent investigator capable of making meaningful scientific contributions.