A Forward Genetic Approach To Studying Glioma Formation and Therapy Resistance

描述(由申请人提供)：高级别胶质瘤是一种破坏性肿瘤，预后差，治疗选择有限。治疗阻力是胶质瘤治疗的一大障碍，患者的生存通常以月为单位进行衡量。彻底了解胶质瘤发生、发展和治疗抵抗的遗传学基础对于开发更好的治疗方法将是重要的。我们一直使用睡美人(SB)转座子系统作为插入突变技术，用于在肉瘤、造血肿瘤和人类癌症小鼠模型的前列腺癌中发现癌症基因。最近，我们发现，尽管大多数受到SB转座子全身动员的小鼠都会发生造血系统疾病，但也有一些小鼠会发展为高级别胶质瘤。我们推测，这些SB诱导的胶质瘤可以用来识别与胶质瘤形成有关的新基因。此外，我们建议修改SB技术，将突变限制在胶质瘤启动细胞，以产生一个新的临床前小鼠模型，用于研究胶质瘤的形成和治疗反应。我们还将在细胞培养模型中使用SB技术作为诱变剂，研究耐药的遗传基础。细胞培养模型也将用于验证SB确定的基因在胶质瘤形成和治疗耐药中的作用。总而言之，SB系统在研究胶质瘤发生和治疗耐药的遗传学方面具有很大的前景。公共卫生相关性：高级别胶质瘤是毁灭性的肿瘤，治疗选择有限，治疗抵抗率高。我们建议使用睡美人转座子技术来识别与胶质瘤形成和治疗耐药有关的新基因。彻底了解胶质瘤发生和发展的遗传学基础对于设计新的更好的治疗方法至关重要。

DESCRIPTION (provided by applicant): High-grade gliomas are devastating tumors with poor prognoses and limited treatment options. Therapy resistance is a great obstacle to glioma treatment and patient survival is generally measured in months. A thorough knowledge of the genetic basis of glioma initiation, progression and therapy resistance will be important for developing better therapies for the disease. We have been using the Sleeping Beauty (SB) transposon system as an insertional mutagenesis technology for cancer gene discovery in sarcomas, hematopoietic tumors and prostate cancer in mouse models of human cancer. Recently, we have discovered that although most mice suffering whole body mobilization of SB transposons develop hematopoietic disease, some also develop high-grade gliomas. We hypothesize that these SB-induced gliomas can be used to identify new genes involved in gliomagenesis. Furthermore, we propose to modify the SB technology to limit mutagenesis to glioma-initiating cells to generate a new pre- clinical murine model for studying glioma formation and therapy response. We will also use the SB technology as a mutagen in cell culture models to study the genetic basis of therapy resistance. Cell culture models will also be used to validate the role of genes identified by SB in glioma formation and therapy resistance. In summary, the SB system holds great promise to study the genetics of gliomagenesis and therapy resistance. PUBLIC HEALTH RELEVANCE: High-grade gliomas are devastating tumors with limited treatment options and high rates of therapy resistance. We propose here to use the Sleeping Beauty transposon technology to identify new genes involved in glioma formation and therapy resistance. A thorough understanding of the genetic basis of glioma initiation and progression is crucial for designing new and better therapies for the disease.