The Role of Bcl2L12 in the Genesis of Malignant Glioma

Bcl2L12 在恶性胶质瘤发生中的作用

基本信息

批准号：
7486342
负责人：
Alexander H. Stegh
金额：
$ 9万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-17 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486342
关键词：
19q Address Alleles Anaplastic astrocytoma Apoptosis Apoptotic Applications Grants Area Astrocytes Binding Biochemical Biological Biological Assay Biological Models Biology Brain Candidate Disease Gene Caspase Cell Lineage Cells Cessation of life Chromosomes Clinical Colon Complement Complementary DNA Computer Simulation Condition Coupled Cultured Cells Data Depth Development Diagnosis Disease Elements Engineering Essential Genes Event Extramural Activities Follicular Lymphoma Foundations Future Gastrointestinal Stromal Tumors Gene Expression Profile Gene Targeting Gene Transfer Techniques Genes Genetic Genetically Engineered Mouse Genome Genomics Genus Cola Glioblastoma Glioma Goals Growth Hodgkin Disease Human In Vitro Inhibition of Apoptosis Investigation Knock-out Knockout Mice Lead Lesion Lymphoma Maintenance Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mesothelioma Microvascular Proliferation Mitochondria Modality Modeling Modification Molecular Molecular Analysis Molecular Profiling Monitor Mus Necrosis Neurons Normal tissue morphology Nucleoplasm Oncogene Proteins Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Physiological Pliability Principal Investigator Property Prostate Protein p53 Proteins RNA Interference Reporting Research Resistance Role Sampling Signal Transduction Specimen Stem cells Structure Subgroup System TP53 gene Technology Testing Therapeutic Therapeutic Intervention Thyroid Gland Tissues Toxic effect Transactivation Transcriptional Activation Transcriptional Regulation Translations Transplantation Up-Regulation Validation base brain tissue c-myc Genes caspase-3 caspase-7 cell type chromatin immunoprecipitation drug development gain of function high throughput screening in vivo in vivo Model indexing inhibitor/antagonist large cell Diffuse non-Hodgkin&apos s lymphoma liposarcoma loss of function lung Carcinoma mouse model mutant neoplastic cell nerve stem cell novel polypeptide pre-clinical programs research study small molecule stem success therapeutic target tumor tumor growth tumor initiation tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most aggressive manifestation of malignant gliomas, are characterized by microvascular proliferation, necrosis, extreme resistance to all extant therapeutic modalities and a neurologically destructive course culminating in death often within 12 months of diagnosis. Major conceptual gaps remain on the mechanistic level including how the classical genetic lesions contribute to these phenotypic aspects. To address this issue, we performed oncogenomic analyses of a large panel of human GBMs by array-CGH and expression profiling in an effort to gain a more comprehensive view of the genetic events underlying GBM development. In the course of characterizing a region of gain on chromosome 19q, we identified Bcl2L12 (for Bcl2-Like-12) as a glioma oncogene that is over-expressed in virtually all GBM samples, yet low or absent in low-grade disease and normal tissue. Extensive biochemical studies have established that Bcl2L12 functions as an anti-apoptotic protein in primary astrocytic cultures by inhibiting post-mitochondrial caspase-3 and caspase-7 activation. Since inhibition of apoptosis at the post- mitochondrial level is known to block apoptosis but promotes necrosis, Bcl2L12 over-expression in GBM may provide a rational explanation for a prime paradox in the biology of this disease - apoptosis resistance yet florid necrosis - and points to Bcl2L12 up-regulation as a key progression event in malignant glioma. In addition to its cytosolic caspase-3/7 inhibitory activity, Bcl2L12 resides in the nucleoplasm where it interacts with p53 and blocks p53-mediated transactivation. To analyze Bcl2L12-modulated pathways in cell culture- based assays in more detail and to genetically validate these findings in vivo, this grant proposal aims to elucidate further the molecular basis of Bcl2L12's oncogenic activity through detailed structure-function analyses. We will employ cell culture-based assays and orthotopic SCID explant tumor models using genetically engineered neuronal stem cells and mature cortical astrocytes to dissect apoptosis- and p53 modulatory activities. Furthermore, we will characterize in depth the molecular mechanism of p53 inhibition that defines yet another oncogenic activity of Bcl2L12 through detailed studies of p53-mediated transcriptional regulation. Finally, the consequences of Bcl2L12 inactivation for the development of GBM will be assessed using conditional Bcl2L12 knockout mice that may serve as an in vivo platform on which to assess consequence of pharmacological inactivation of Bcl2L12 for malignant glioma therapy. The continued lack of success in treating high-grade gliomas has prompted a reevaluation of all aspects of glioma drug development. This grant proposal aims to specifically address the currently unmet needs in the development of effective glioma therapies by refining the molecular understanding of the disease and by developing more accurate in vitro and in vivo glioma model system.

描述（由申请人提供）：胶质母细胞瘤多形（GBM）是恶性神经胶质瘤的最具侵略性的表现，其特征是微血管增殖，坏死，对所有现有治疗方式的极端耐药性和对神经学上的神经学上的极端耐药性，并且在诊断后的12个月内经常在12个月内的死亡中加剧。主要的概念差距仍然存在于机械水平上，包括经典遗传病变如何促进这些表型方面。为了解决这个问题，我们通过阵列-CGH和表达分析对大量人类GBM进行了致癌分析，以更全面地了解GBM开发的基因事件。在表征19q染色体上增加区域的过程中，我们将BCL2L12（对于Bcl2样子12）确定为一种胶质瘤癌基因，在几乎所有GBM样品中都过表达，但在低级疾病和正常组织中却低或不存在。广泛的生化研究已经确定，通过抑制线粒体后caspase-3和caspase-7激活，BCL2L12在原代星形胶质细胞培养物中起抗凋亡蛋白的作用。 Since inhibition of apoptosis at the post- mitochondrial level is known to block apoptosis but promotes necrosis, Bcl2L12 over-expression in GBM may provide a rational explanation for a prime paradox in the biology of this disease - apoptosis resistance yet florid necrosis - and points to Bcl2L12 up-regulation as a key progression event in malignant glioma.除了其胞质caspase-3/7抑制活性外，Bcl2L12还驻留在核质中，与p53相互作用并阻止p53介导的反式激活。为了更详细地分析基于细胞培养的测定中的BCL2L12调节途径，并在遗传上验证了这些发现，该赠款提案旨在通过详细的结构 - 函数分析来进一步阐明BCL2L12致癌活性的分子基础。我们将使用基于基因的神经元干细胞和成熟的皮质星形胶质细胞使用基于细胞培养的测定和原位SCID外植体肿瘤模型，以剖析细胞凋亡和p53调节活性。此外，我们将通过对p53介导的转录调节的详细研究来深入p53抑制的分子机制，从而定义了Bcl2L12的另一种致癌活性。最后，将使用条件BCL2L12基因敲除小鼠评估BCL2L12灭活对GBM的发展的后果，该小鼠可能是一个体内平台，以评估BCL2L12对恶性神经胶质瘤治疗的药理失活的结果。持续缺乏治疗高级神经胶质瘤的成功促使对神经胶质瘤药物开发的各个方面进行了重新评估。该赠款提案旨在通过完善对疾病的分子理解并开发更准确的体外和体内胶质瘤模型系统来特别解决有效神经胶质瘤疗法的目前未满足的需求。