Role of Ascl1 in glioma

Ascl1 在神经胶质瘤中的作用

基本信息

批准号：
8448948
负责人：
Tou Yia Vue
金额：
$ 5.22万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448948
关键词：
Adult Affect Alleles Anaplastic astrocytoma Astrocytoma Autonomic nervous system BHLH Protein Back Biological Assay Biology Brain Brain Neoplasms Brain region Cell Cycle Cell Fraction Cell Maintenance Cell Separation Cells Data Development Diagnostic Neoplasm Staging Disease Embryonic Development Equilibrium Fluorescence Fluorescence-Activated Cell Sorting Gene Expression Regulation Genes Genetic Glioblastoma Glioma Gliomagenesis Goals Heterogeneity Hippocampus (Brain)Immunohistochemistry In Vitro Incidence Knowledge Lead Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Measures Methods Modeling Molecular Molecular Profiling Mus NF1 gene Natural regeneration Nervous system structure Neural tube Neuraxis Neurosecretory Systems Pathogenesis Play Proliferating Property Reporter Research Research Proposals Role SCID Mice Signal Transduction Staging Stem cells Testing Time Transplantation Tumor Biology Tumor Suppressor Genes Tumor stage Tumor-Derived adult neurogenesis cancer stem cell cell fate specification combat dentate gyrus genetic regulatory protein gliogenesis in vivo insight knock-down lateral ventricle lung small cell carcinoma mouse model neoplastic cell nerve stem cell neurogenesis new therapeutic target notch protein oligodendrocyte precursor precursor cell self-renewal subventricular zone therapeutic development tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Primary malignant gliomas are incurable brain tumors that affect thousands of people every year. Although alteration of oncogenes and tumor suppressors genes have been described to contribute to the pathogenesis of gliomas, very little is known about the biology of glioma development or the genetic mechanisms that are essential for tumor formation and progression. Ascl1, a basic-helix-loop-helix (bHLH) transcription factor, is aberrantly upregulated in a number of cancers, including lung cancers with neuroendocrine features and malignant astrocytoma. Mouse models of malignant astrocytoma recently indicated that neural progenitors may be the cells of origin for glioma. Given that Ascl1 is expressed in neural progenitors during development as well as in the adult brain, and was recently shown to directly regulate cell cycle regulators, it is hypothesized that Ascl1 plays an important role in gliomagenesis. Preliminary evidence for the proposed project demonstrates that Ascl1 is highly expressed in a subset of cells of an early stage brain tumor and in cells at the periphery of a terminal stage brain tumor of a mouse model of malignant astrocytoma. The aims of the proposed project include genetic strategies to induce and directly visualize tumor development in the brains of mice, immunohistochemistry to describe the expression of Ascl1 in tumors at multiple stages of development, and use of fluorescence activated cell sorting (FACS) to isolate and characterize the tumorigenic properties of Ascl1-expressing tumor cells in vitro and in vivo. Finally, the requirement for Ascl1 for tumor formation and progression in this mouse model of glioma will be directly tested by conditional deletion of Ascl1. The culmination of this study will provide new insights into the heterogeneity and molecular mechanisms of glioma tumors.

描述（由申请人提供）：原发性恶性神经胶质瘤是无法治愈的脑肿瘤，每年影响数千人。尽管癌基因和抑癌基因的改变被认为有助于神经胶质瘤的发病机制，但人们对神经胶质瘤发育的生物学或肿瘤形成和进展所必需的遗传机制知之甚少。 Ascl1 是一种碱性螺旋环螺旋 (bHLH) 转录因子，在多种癌症中异常上调，包括具有神经内分泌特征的肺癌和恶性星形细胞瘤。恶性星形细胞瘤的小鼠模型最近表明神经祖细胞可能是神经胶质瘤的起源细胞。鉴于 Ascl1 在发育过程中的神经祖细胞以及成人大脑中表达，并且最近被证明可以直接调节细胞周期调节因子，因此推测 Ascl1 在神经胶质瘤发生中发挥重要作用。该项目的初步证据表明，Ascl1 在早期脑肿瘤的一部分细胞以及恶性星形细胞瘤小鼠模型的晚期脑肿瘤周围的细胞中高度表达。该项目的目标包括诱导和直接可视化小鼠大脑中肿瘤发展的遗传策略、描述肿瘤多个发展阶段 Ascl1 表达的免疫组织化学，以及使用荧光激活细胞分选 (FACS) 来分离和观察肿瘤的发展。表征 Ascl1 表达肿瘤细胞的体外和体内致瘤特性。最后，将通过条件性删除 Ascl1 来直接测试该神经胶质瘤小鼠模型中肿瘤形成和进展对 Ascl1 的需求。这项研究的高潮将为神经胶质瘤的异质性和分子机制提供新的见解。