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

这项建议关注的是核因子I A(NFIA)的潜在作用，NFIA是一种受神经胶质细胞谱系限制的因子 发育调控基因，在胶质瘤发病机制中的作用。NFIA转录因子是 中枢神经系统内神经胶质细胞的识别和星形胶质细胞分化的规范。我的初步数据显示NFIA是 在人类星形细胞瘤中高表达，NFIA高表达与生存期的提高有关。 然而，在实验系统中，过表达NFIA增加了U87人GBM的集落形成 软琼脂中的细胞株和U87小鼠脑内肿瘤的加速生长。相反， NFIA(ShRNAi)的敲除导致软琼脂中的菌落变小，细胞在培养中的生长减少，以及 抑制小鼠U87原位肿瘤的生长。这些发现表明NFIA在神经胶质瘤中起作用。 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，这可能取决于NFIA剪接变异体 在肿瘤中表达。1因此，提出以下具体目标： 1.确定NFIA功能增益(GOF)/功能丧失(LOF)和剪接变异体在 星形细胞瘤的增殖和凋亡 2.检测NFIA GOF/LOF和剪接变异体对星形细胞瘤迁移和侵袭的影响 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。 我在萨班研究所(SRI)建立了高度支持的指导关系，网址为 洛杉矶儿童医院(CHLA)与Anat Erdreich-Epstein博士和Yves DeClerck博士在癌症中 计划和大卫·沃伯顿的发育生物学计划。此外，1个已经形成了密切的联系 与加州理工大学的大卫·安德森博士合作。这项提议得到了导师们的全力支持， 部门和机构。SRI的全部资源和核心都可以用于我的工作。我计划这样做 将我职业生涯的很大一部分时间投入到基础研究和翻译研究中，希望能得到我的发现 在未来转化为临床医学。1打算将神经肿瘤学的原理和 神经发育生物学：寻找治疗神经胶质瘤新方法的新协同方法 心理治疗。我已经有了一套有希望的初步数据和我目前的具体实验设计 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医生兼科学家。 相关性(请参阅说明)： 实现我的目标将解释NFIA表达与更好的似乎不同的联系 患者的结果，但在我的实验系统中加速了肿瘤的生长，因此将有助于发现 它在人类胶质瘤中的作用及其背后的分子机制。这一知识将支持未来 致力于开发针对恶性胶质瘤的治疗方法。

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, overexpression 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. 1 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 Childrens 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 1 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. 1 intend to combine the principles of Neurooncology and Neurodevelopmental Biology in a novel synergistic approach towards finding new approaches to glioma therapy. 1 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. RELEVANCE (See instructions): 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.