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

这项建议的重点是核因子I A（NFIA）的潜在作用， 发育调控基因在胶质瘤发病机制中的作用。NFIA转录因子对于 CNS中神经胶质细胞身份和星形胶质细胞分化的规范。我的初步数据显示NFIA是 NFIA在人类星形细胞瘤中高度表达，且较高的NFIA表达与生存期的改善相关。 然而，在实验系统中，NFIA的过表达增加了U87人GBM的集落形成 软琼脂中的U87细胞系和小鼠脑中U87颅内肿瘤的加速生长。相反地， 敲低NFIA（shRNAi）导致软琼脂中较小的集落，降低培养物中的细胞生长， 抑制小鼠原位U87肿瘤的生长。这些发现表明NFIA在胶质瘤中起作用， 生长，但可能有差异，肿瘤抑制和肿瘤促进作用。因此我假设 NFIA在星形细胞瘤生长中起作用，这可能取决于NFIA剪接变体 在肿瘤中表达。1因此，提出以下具体目标： 1.为了确定NFIA功能获得性（GOF）/功能丧失性（LOF）和剪接变异体在 星形细胞瘤增殖和凋亡 2.研究NFIA GOF/LOF和剪接变异体对星形细胞瘤迁移和侵袭的影响 3.确定剪接变体和NFIA的GOF/LOF操作对体内GBM肿瘤的影响。 我在萨班研究所（SRI）建立了高度支持的指导关系， 洛杉矶儿童医院（CHLA）与Anat Erdreich-Epstein和Yves DeClerck博士在癌症 程序和大卫沃伯顿在发育生物学程序。此外，1已形成密切 与加州理工学院的大卫安德森博士合作。这一建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用于我的工作。我计划 我把我职业生涯的很大一部分投入到基础和转化研究中，希望能有我的发现 在未来转化为临床医学。1.打算将神经肿瘤学的原理与联合收割机 神经发育生物学在寻找胶质瘤新方法的新协同方法中 疗法我已经有了一套有希望的初步数据和具体的实验设计， 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， 成为一名独立的科学家。 相关性（参见说明）： 实现我的目标将解释NFIA表达与更好的 结果，但在我的实验系统中加速了肿瘤的生长，因此将有助于揭示 它在人类胶质瘤中的作用及其潜在的分子机制。这些知识将支持未来 致力于开发恶性神经胶质瘤的治疗方法。

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.