Astrocytic Cancers: How, When, Where?

描述(由申请人提供)： 星形细胞瘤是人类最常见的脑肿瘤，包括低级别星形细胞瘤(II级)、间变性星形细胞瘤(III级)和胶质母细胞瘤(IV级)。主要是因为它们的弥漫性，这些癌症没有有效的治疗方法，对它们的发生机制(S)也知之甚少。例如，我们不了解易感靶细胞(S)的性质和微环境的影响，不了解遗传损伤和细胞/组织反应之间的因果关系，也不了解从低度恶性向高度恶性进展的分子和细胞学基础。由于即使是正常的发育和动态平衡机制也很难在哺乳动物复杂的大脑环境中辨别出来，因此需要实验动物模型来理解星形细胞癌的复杂性，并为其治疗开发合理的治疗方法。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领域的最新进展，以及合适的临床前小鼠模型的发展，为解决这些问题提供了基础。此外，老鼠建模、基因组学和成像方法方面的新技术进步也促进了这类研究。 目前的提案旨在通过利用这些不同的区域来启动对星形细胞肿瘤发生的全面评估。在这里，我们将探索在特定的细胞靶点和大脑的特定微环境中引入基因改变的生物学后果。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(Van Dyke)和co-Pi(Gutmann)已经利用不同的策略开发了重要的宝石星形细胞瘤模型。前者在星形细胞系中PRB通路失活后发展为完全外显的GEM III级星形细胞瘤，而后者在同一系中由于RAS激活而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老鼠和人类疾病之间的相似程度。此外，我们将努力为我们和其他人产生的数据建立数据库和其他共享机制。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；加州大学洛杉矶分校)；Johnson博士(小动物成像；杜克大学)；Bullitt博士(血管特性成像；UNC)；Lin博士(肿瘤特性的核磁共振分析；UNC)；Baker博士(表达分析；加州大学佛罗里达分校)和Pevney博士(发育神经生物学；UNC)。

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).