A Forward Genetic Approach To Studying Glioma Formation and Therapy Resistance

研究神经胶质瘤形成和治疗耐药性的正向遗传学方法

• 批准号: 7827991
• 负责人: Lara S Collier
• 金额: $ 20.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827991
• 关键词: Astrocytes; Astrocytoma; Biological Markers; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Cells; Data; Disease; Dissection; Drug Delivery Systems; Genes; Genetic; Genetic Screening; Glioblastoma; Glioma; Gliomagenesis; Goals; Grant; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Insertional Mutagenesis; Investigation; Knowledge; Lasers; Malignant neoplasm of prostate; Measures; Methylation; Modeling; Molecular; Mus; Mutagenesis; Mutagens; O(6)-Methylguanine-DNA Methyltransferase; Oncogenes; Patients; Penetrance; Pharmaceutical Preparations; Radiation; Refractory Disease; Resistance; Role; Screening for cancer; Site; Sleeping Beauty; Study models; System; Technology; Testing; Transgenic Organisms; Transposase; Tumor Suppressor Genes; base; chemotherapy; design; effective therapy; gene discovery; glioma cell line; human cancer mouse model; improved; neoplastic cell; novel; outcome forecast; pre-clinical; public health relevance; response; sarcoma; temozolomide; therapeutic target; therapy resistant; tool; tumor

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.

描述（由申请人提供）：高级神经胶质瘤是毁灭性的肿瘤，预后不良和治疗选择有限。耐药性是神经胶质瘤治疗的重要障碍，并且通常在几个月内测量患者的生存率。对神经胶质瘤起始，进展和抗治疗性的遗传基础的透彻了解对于为疾病开发更好的疗法至关重要。我们一直在人类癌症小鼠模型中使用“睡美人（SB）转座系统”作为肉瘤，造血肿瘤和前列腺癌的癌症基因发现的插入诱变技术。最近，我们发现，尽管大多数患有SB转座子全身动员的小鼠会发展出造血性疾病，但有些也会发展出高度的神经胶质瘤。我们假设这些SB诱导的神经膜瘤可用于鉴定涉及胶质促性的新基因。此外，我们建议修改SB技术，以将诱变限制为神经胶质瘤发射细胞，以生成一种新的临床前鼠模型，以研究神经胶质瘤形成和治疗反应。我们还将使用SB技术作为细胞培养模型中的诱变剂来研究抗治疗抗性的遗传基础。细胞培养模型还将用于验证SB在神经胶质瘤形成和治疗耐药性中鉴定的基因的作用。总而言之，SB系统具有研究神经胶质作用和耐药性的遗传学的巨大希望。公共卫生相关性：高级神经胶质瘤是毁灭性的肿瘤，治疗方案有限，耐药率高。我们在这里建议使用睡美人的转座子技术来识别与胶质瘤形成和耐药性有关的新基因。对神经胶质瘤起始和进展的遗传基础的透彻理解对于为疾病设计新的，更好的疗法至关重要。