Astrocytic Cancers: How, When, Where?

描述（由申请人提供）： 星形细胞瘤，包括低级别星形细胞瘤（II级）、间变性（高级别）星形细胞瘤（III级）和胶质母细胞瘤（IV级），是最常见的人类脑肿瘤。主要是因为它们的扩散性质，对这些癌症没有有效的治疗方法，并且对它们发展的机制知之甚少。例如，我们不了解易感靶细胞和微环境影响的性质，遗传病变和细胞/组织反应之间的因果关系，也不了解从低度恶性进展到高度恶性的分子和细胞基础。因为即使是正常的发育和稳态机制是很难辨别的复杂环境中的哺乳动物大脑，实验动物模型需要了解星形胶质细胞癌的复杂性，并制定合理的治疗方法。最近在脑细胞谱系、星形胶质细胞生物学、人类星形细胞瘤遗传学以及适当的临床前小鼠模型的开发等领域的进展为解决这些问题提供了基础。此外，小鼠建模、基因组学和成像方法学方面的新兴技术进步也促进了此类研究。 目前的提案旨在通过利用这些不同的领域来启动对星形细胞肿瘤发生的全面评估。在这里，我们将探讨引入特定细胞靶点和大脑特定微环境中的遗传改变的生物学后果。生物分析将包括分子和细胞生物学方法，以及细胞、组织和活体动物成像。PI（货车Dyke）和co-PI（Gutmann）已经利用不同的策略开发了重要的GEM星形细胞瘤模型。前一种模型在星形细胞谱系中pRb通路失活后发展为GEM III级星形细胞瘤，具有完全失活率，而后者在相同谱系内Ras激活后发展为高级别星形细胞瘤和胶质母细胞瘤。在我们继续探索星形胶质细胞癌的基本遗传和生物学机制的同时，我们还将利用基因组和成像工具来监测小鼠和人类疾病之间的相似性程度。此外，我们将努力建立数据库和其他共享机制，以共享我们和其他方生成的数据。这些工作的合作者包括Ellisman博士（细胞和组织成像;数据库开发; UCSD）、约翰逊博士（小动物成像;杜克大学）、Bullitt博士（血管特性成像; MRI）、Lin博士（肿瘤特性的MRI分析; MRI）、Baker博士（表达分析; U。佛罗里达）和Pevney（发育神经生物学;）。

DESCRIPTION (provided by applicant): Astrocytomas, including low grade astrocytoma (grade II), anaplastic (high grade) astrocytoma (grade III) and glioblastoma (grade IV), are the most common human brain tumor. Primarily because of their diffuse nature, there is no effective treatment for these cancers, and little is known about the mechanism(s) by which they develop. For example, we do not understand the nature of susceptible target cell(s) and microenvironment influences, the cause and effect relationships between genetic lesions and cell/tissue responses, nor the molecular and cellular basis for progression from low to high-grade malignancy. Because even normal developmental and homeostatic mechanisms are difficult to discern within the intricate environment of the mammalian brain, experimental animal models are required to understand the complexities of astrocytic cancers and to develop reasonable therapies for its treatment. Recent advances in the areas of brain cell lineages, astrocyte biology, human astrocytoma genetics, and the development of appropriate preclinical mouse models have provided a foundation for addressing these problems. Furthermore, such studies are facilitated by emerging technological advances in mouse modeling, genomics and imaging methodologies. The current proposal aims to launch a comprehensive assessment of astrocytic tumorigenesis by drawing on these diverse areas. Here we will probe the biological consequences of genetic alterations introduced into specific cellular targets and within specific microenvironments of the brain. Biological analysis will include molecular and cell biological approaches coupled with cellular, tissue and live animal imaging. The PI (Van Dyke) and co-PI (Gutmann) have already developed important GEM astrocytoma models utilizing distinct strategies. The former model develops GEM grade III astrocytoma with complete penetrance after inactivation of the pRb pathway in the astrocytic lineage, while the latter develops high grade astrocytoma and glioblastoma upon Ras activation within the same lineage. While we continue to probe basic genetic and biological mechanisms of astrocytic cancers we will also utilize genomic and imaging tools to monitor the extent of similarities between the mouse and human diseases. In addition we will work to establish databases and other sharing mechanisms for the data generated by us and others. Collaborators in these efforts include Drs. Ellisman (cellular and tissue imaging; database development; UCSD), Johnson (small animal imaging; Duke University); Bullitt (imaging of vessel properties; UNC); Lin (MRI analysis of tumor properties; UNC); Baker (expression analysis; U. Florida) and Pevney (developmental neurobiology; UNC).