Antigen specific modeling of glioma immunotherapy

描述（由申请人提供）：本提案旨在为Andrew T. Parsa博士提供五年的学术医师和基础科学家发展的机会。Parsa博士是加州大学旧金山分校神经外科的助理教授，对脑肿瘤有临床和科学的兴趣。他是一名执业神经外科医生，他将把50-60%的学术努力花在一个由他的导师Abul Abbas博士指导的科学训练项目上。Dr. Parsa的科学发展将通过研究生课程、研究研讨会和一个假设驱动的研究项目来促进，Dr. Parsa将作为首席研究员主要负责该项目。该项目名为“胶质瘤免疫治疗的抗原特异性建模”，旨在解决中枢神经系统中有关免疫的基本问题。本实验旨在验证局部抗肿瘤免疫与颅内神经胶质肿瘤负荷负相关的假设。神经胶质细胞在维持神经系统功能完整性中起着重要的作用。当神经外细胞如神经胶质细胞转变为恶性肿瘤时，就会导致神经系统疾病。免疫治疗是传统辅助治疗的一种有吸引力的替代方法，因为它可以特异性地靶向恶性胶质细胞，同时保留周围细胞（包括神经元）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)定义T细胞对颅内胶质肿瘤特异性抗原反应的动力学，位置和大小，2)分析肿瘤特异性抗原外周刺激后中枢神经系统中T细胞的积累，以及3)表征T细胞对肿瘤特异性抗原运输到中枢神经系统后的反应。实现这些目标将有助于更好地理解抗原特异性免疫介导的抗中枢神经系统肿瘤的作用。重要的是，这些目标将使研究人员能够适应和测试一个模型，该模型概括了自发产生的神经胶质肿瘤的人类状况。这些目标的重点性质，结合UCSF的临床和科学环境，将为PI提供宝贵的培训经验。这项提案的长期目标是促进Parsa博士成为一名能够做出有意义的科学贡献的独立研究者。

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.