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。治疗耐药性是胶质瘤治疗的一个巨大障碍，患者的生存期通常以月为单位。深入了解胶质瘤发生、发展和耐药的遗传基础对于开发更好的治疗方法具有重要意义。我们一直在使用睡美人（SB）转座子系统作为插入诱变技术的癌症基因发现在肉瘤，造血肿瘤和前列腺癌的小鼠模型中的人类癌症。最近，我们发现，虽然大多数小鼠遭受全身动员SB转座子发展造血系统疾病，一些也发展高级别胶质瘤。我们假设这些SB诱导的胶质瘤可用于鉴定参与胶质瘤发生的新基因。此外，我们建议修改SB技术以将诱变限制在神经胶质瘤起始细胞，从而产生用于研究神经胶质瘤形成和治疗反应的新的临床前小鼠模型。我们还将使用SB技术作为细胞培养模型中的诱变剂，以研究治疗抗性的遗传基础。细胞培养模型也将用于验证SB鉴定的基因在胶质瘤形成和治疗抗性中的作用。总之，SB系统对研究胶质瘤发生和治疗抗性的遗传学有很大的希望。公共卫生相关性：高级别胶质瘤是一种具有破坏性的肿瘤，治疗选择有限，治疗耐药率高。我们在这里建议使用睡美人转座子技术，以确定新的基因参与胶质瘤的形成和治疗耐药性。深入了解胶质瘤发生和发展的遗传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.