The role of microglia and macrophages in the development of brain tumors

项目概述：该提案描述了一个为期5年的职业发展计划，其目标是培养菲利普斯博士成为一名独立的学术研究者。项目发起人Zena Werb博士将提供主要指导。Werb博士是国际公认的肿瘤微环境专家，在培养独立科学家方面有着杰出的记录。该项目的共同发起人David Rowitch博士是国际公认的脑肿瘤发展专家，他致力于培养临床科学家。除了博士。咨询委员会成员Werb和Rowitch将提供额外的科学和职业发展相关指导。该研究计划将解决小胶质细胞和巨噬细胞加速脑肿瘤进展和浸润的假设。小胶质细胞和巨噬细胞是脑肿瘤微环境的重要组成部分；然而，它们的激活表型和功能尚不清楚。在这个项目中，小胶质细胞和巨噬细胞在浸润性胶质肿瘤发展中的作用将在三个具体目标中进行评估。首先，我将研究浸润性胶质肿瘤中小胶质细胞和巨噬细胞随时间的激活模式。研究将使用强大的小鼠浸润性胶质瘤模型进行，结果将在人类肿瘤组织中得到证实。第二，我将确定小胶质细胞和巨噬细胞是否促进肿瘤细胞浸润。使用新的成像技术，我将监测免疫细胞和肿瘤细胞的动态相互作用。第三，我将通过消耗或修饰小胶质细胞和巨噬细胞对脑肿瘤的反应来确定其在体内的意义。研究训练也将包括研究伦理、肿瘤生物学、先进分子技术和肿瘤免疫学的正式教学计划。UCSF病理学部门完全致力于菲利普斯博士的职业发展，UCSF为独立内科科学家的培训提供了理想的环境。相关性：据估计，2007年美国将有20,500人被诊断患有脑癌和神经系统癌。尽管目前的治疗方法浸润性胶质瘤，最常见的原发性脑肿瘤类型，继续发展，往往是致命的。本项目提出的研究将对微环境中促进脑肿瘤进展和浸润的因素产生重要的见解，并可能有助于开发新的胶质瘤治疗方法。

DESCRIPTION (provided by applicant): Project Summary: This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Phillips for the role of an independent academic investigator. The project sponsor, Dr. Zena Werb, will provide the principle guidance. Dr. Werb is an internationally recognized expert on the tumor microenvironment and has a distinguished record of training independent scientists. The project co-sponsor, Dr. David Rowitch, is an internationally recognized expert on brain tumor development with a demonstrated commitment to training clinician-scientists. In addition to Drs. Werb and Rowitch, the members of the advisory committee will provide additional scientific and career development related guidance. The research program will address the hypothesis that microglia and macrophages accelerate brain tumor progression and infiltration. Microglia and macrophages are a significant component of the brain tumor microenvironment; however, their activation phenotype and function are unclear. In this project, the role of microglia and macrophages in the development of infiltrating glial tumors will be assessed in three specific aims. First, I will examine the activation patterns of microglia and macrophages in infiltrating glial tumors over time. Studies will be performed using a robust murine model for infiltrating glioma and the results will be confirmed in human tumor tissue. Second, I will determine whether microglia and macrophages promote tumor cell infiltration. Using novel imaging technology I will monitor the dynamic interactions of immune cells and tumor cells. Third, I will determine the in vivo significance of the microglial and macrophage response to brain tumor by depleting it or modifying it. The research training will also include a formal didactic program in research ethics, tumor biology, advanced molecular techniques, and tumor immunology. The UCSF Pathology Department is fully committed to Dr. Phillips' career development and UCSF provides an ideal setting for the training of independent physician scientists. Relevance: In 2007, it is estimated that 20,500 individuals will be diagnosed with cancer of the brain and nervous system in the United States. Despite current therapies infiltrating gliomas, the most common type of primary brain tumor, continues to progress and is often fatal. The research proposed in this project will yield important insight into the factors in the microenvironment that contribute to brain tumor progression and infiltration and potentially may aid in the development of new therapies for glioma.