Antigen specific modeling of glioma immunotherapy

描述（由申请人提供）：本提案旨在为Andrew T. Parsa有机会在五年内发展成为学术医生和基础科学家。Parsa博士是UCSF神经外科系的助理教授，对脑肿瘤有临床和科学兴趣。他是一名执业神经外科医生，他将花费50-60%的学术精力在他的导师Abul Abbas博士监督的科学培训计划中。Parsa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，Parsa博士将主要负责作为主要研究者。该项目名为“胶质瘤免疫治疗的抗原特异性建模”，解决了中枢神经系统免疫的基本问题。所提出的实验旨在检验局部抗肿瘤免疫与颅内神经胶质肿瘤负荷负相关的假设。神经胶质细胞整体参与维持神经系统的功能完整性。当神经元外细胞如神经胶质转化为恶性肿瘤时，可能导致神经系统疾病。免疫疗法是常规辅助疗法的有吸引力的替代方案，因为它可以特异性靶向恶性胶质细胞，同时保留周围细胞（包括神经元）的功能。在抗原特异性神经胶质瘤转基因模型的背景下，将追求以下特定目的：1）确定T细胞对颅内神经胶质肿瘤特异性抗原应答的动力学、位点和幅度，2）分析肿瘤特异性抗原外周刺激后CNS中T细胞的累积，3）表征运输至CNS后T细胞对肿瘤特异性抗原的应答。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对CNS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，该模型重现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。该提案的长期目标是促进Parsa博士发展成为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.