Role of Nuclear Factor I A (NFIA) gene in glioma

描述(由申请人提供)：项目摘要：这项建议集中于核因子I A(NFIA)在胶质瘤发病机制中的潜在作用，NFIA是一种神经胶质细胞系限制性发育调节基因。NFIA转录因子是中枢神经系统神经胶质细胞识别和星形胶质细胞分化所必需的转录因子。我的初步数据显示，NFIA在人类星形细胞瘤中高表达，高表达与提高存活率有关。然而，在实验系统中，NFIA的过表达增加了U87人GBM细胞系在软琼脂中的集落形成，并加速了U87脑内肿瘤的生长。相反，NFIA(ShRNAi)的敲除导致软琼脂中的菌落较小，减少了培养中的细胞生长，并抑制了小鼠原位U87肿瘤的生长。这些发现表明，NFIA在胶质瘤生长中有一定作用，但可能具有不同的、抑制肿瘤和促进肿瘤的作用。因此，我假设NFIA在星形细胞瘤的生长中起作用，这可能依赖于肿瘤中表达的NFIA剪接变体。因此，我提出以下具体目标：1)确定NFIA功能获得/功能丧失(GOF/LOF)和剪接变异体在星形细胞瘤增殖和凋亡中的作用。2)研究NFIA、GOF/LOF和剪接变异体对星形细胞瘤侵袭转移的影响。3)研究NFIA的剪接变异体和GOF/LOF操作对小鼠肾小管上皮细胞瘤的影响。我在洛杉矶儿童医院的萨班研究所(SRI)与癌症项目的Anat Erdreich-Epstein博士和Yves DeClerck博士以及发育生物学项目的David Warburton博士建立了高度支持的指导关系。此外，我还与加州理工大学的大卫·安德森博士建立了密切的合作关系。这项建议得到了导师、部门和机构的全力支持。SRI的全部资源和核心都可以用于我的工作。我计划将我职业生涯的很大一部分时间投入到基础和转化性研究中，希望在未来将我的发现转化为临床医学。我打算将神经肿瘤学和神经发育生物学的原理结合起来，以一种新的协同方法来寻找胶质瘤治疗的新方法。我已经有了一套有希望的初步数据和具体的实验设计，我现在的研究项目，以及优秀的导师和合作者，这将有助于我的职业目标，成为一名独立的内科科学家。 公共卫生相关性：实现我的目标将解释NFIA表达与患者更好的结果似乎存在差异的关联，但在我的实验系统中，肿瘤加速生长，从而将有助于揭示它在人类胶质瘤中的作用及其背后的分子机制。这些知识将支持未来旨在开发针对恶性胶质瘤的治疗方法的工作。

DESCRIPTION (provided by applicant): Project Summary: This proposal focuses on the potential role of Nucear Factor I A (NFIA), a glial lineage-restricted developmental regulatory gene, in glioma pathogenesis. NFIA transcription factor is essential for specification of glial identity and astrocyte differentiation in the CNS. My preliminary data show that NFIA is expressed highly in human astrocytomas and higher NFIA expression is associated with improved survival. In experimental systems, however, over-expression of NFIA increased colony formation of U87 human GBM cell line in soft agar and accelerated growth of U87 intracranial tumors in mouse brains. Conversely, knockdown of NFIA (shRNAi) led to smaller colonies in soft agar, reduced cell growth in culture, and inhibited growth of orthotopic U87 tumors in mice. These findings suggest that NFIA has a role in glioma growth but may have differential, tumor-suppressive and tumor-promoting effects. I therefore hypothesize that NFIA has a role in astrocytoma growth, which may depend on the NFIA splice variants expressed in the tumors. I therefore propose the following Specific Aims: 1) To determine the effect of NFIA gain-of-function (GOF)/loss-of-function (LOF) and splice variants in astrocytoma proliferation and apoptosis. 2) To examine the effect of NFIA GOF/LOF and splice variants on astrocytoma migration and invasion. 3) To determine the effect of splice variants and GOF/LOF manipulation of NFIA on GBM tumors in vivo. I have established highly supportive mentoring relationships at The Saban Research Institute (SRI) at Children's Hospital Los Angeles (CHLA) with Drs. Anat Erdreich-Epstein and Yves DeClerck in the Cancer program and David Warburton in Developmental Biology program. In addition I have formed close collaboration with Drs. David Anderson at Caltech. This proposal is fully supported by mentors, department, and institution. The full resources and cores of the SRI are available for my work. I plan to devote a significant part of my career to basic and translational research with the hope to have my findings translated into clinical medicine in the future I intend to combine the principles of Neurooncology and Neurodevelopmental Biology in a novel synergistic approach towards finding new approaches to glioma therapy. I already have a promising set of preliminary data and concrete experimental design for my current research project, as well as outstanding mentors and collaborators, which will facilitate my career goal to become an independent physician-scientist. Public Health Relevance: Achieving my Aims will explain the seemingly divergent association of NFIA expression with better outcome in patients, but accelerated tumor growth in my experimental system, and will thus help uncover its role in human gliomas and the molecular mechanism underlying it. This knowledge will support future work aimed at development of treatments against malignant gliomas.