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

核因子 I A (NFIA) 基因在神经胶质瘤中的作用

• 批准号: 7913865
• 负责人: Hae-Ri Song
• 金额: $ 17.33万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913865
• 关键词: Genes; Glioma; Role; human NFIA protein

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.

描述（由申请人提供）：项目摘要：该提案重点介绍了核因子I A（NFIA）的潜在作用，即神经胶质谱系限制的发育调节基因在神经胶质瘤发病机理中的潜在作用。 NFIA转录因子对于中枢神经系统中的神经胶质身份和星形胶质细胞分化至关重要。我的初步数据表明，NFIA在人类星形胶质细胞瘤中高度表达，较高的NFIA表达与改善的生存有关。 然而，在实验系统中，NFIA的过表达增加了软琼脂中U87人GBM细胞系的落形成，并加快了小鼠大脑中U87颅内肿瘤的生长。相反，NFIA（SHRNAI）的敲低导致软琼脂中的菌落较小，培养细胞的生长降低，并抑制了小鼠原位U87肿瘤的生长。这些发现表明，NFIA在神经胶质瘤的生长中起作用，但可能具有差异，抑制肿瘤和肿瘤促进作用。因此，我假设NFIA在星形细胞瘤生长中起作用，这可能取决于肿瘤中表达的NFIA剪接变体。因此，我提出以下具体目的：1）确定NFIA功能获得（GOF）/功能丧失（LOF）和剪接变体在星形胶质细胞瘤增殖和凋亡中的影响。 2）检查NFIA GOF/LOF和剪接变体对星形细胞瘤迁移和侵袭的影响。 3）确定剪接变异和GOF/LOF操纵NFIA对体内GBM肿瘤的影响。 我已经在洛杉矶儿童医院（CHLA）的Saban Research Institute（SRI）建立了高度支持的指导关系。 Anat Erdreich-Epstein和Yves在《癌症计划》和David Warburton的发育生物学计划中。此外，我还与Drs建立了密切合作。加州理工学院的大卫·安德森（David Anderson）。该建议得到导师，部门和机构的完全支持。 SRI的全部资源和核心可用于我的工作。我计划将职业生涯的很大一部分投入基础和翻译研究，希望将来能够将我的发现转化为临床医学，我打算将神经机学和神经发育生物学的原理结合在一起，以在一种新的协同方法中找到新的方法进行神经胶质瘤治疗的方法。我已经为我当前的研究项目以及杰出的导师和合作者提供了一套有希望的初步数据和具体的实验设计，这将促进我的职业目标成为独立的医师科学家。 公共卫生的相关性：实现我的目标将解释NFIA表达与患者更好的结果的看似不同的关联，但在我的实验系统中加速了肿瘤的生长，因此将有助于发现其在人神经胶质瘤中的作用和其基于其的分子机制。这些知识将支持旨在开发针对恶性神经胶质瘤治疗的未来工作。