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: 7888171
• 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/7888171
• 关键词: Adult; Agar; Apoptosis; Astrocytes; Astrocytoma; Biology; Brain; Brain Neoplasms; Cell Culture Techniques; Cell Line; Cells; Child; Clinical Medicine; Collaborations; Complement; Complex; Data; Databases; Development; Developmental Biology; Epidermal Growth Factor Receptor; Exhibits; Experimental Designs; Fibrinogen; Future; Gene Family; Genes; Glioblastoma; Glioma; Goals; Growth; Health; Human; Implant; In Vitro; Institution; Intracranial Neoplasms; Knowledge; Link; Los Angeles; Malignant Glioma; Malignant Neoplasms; Mentors; Mining; Molecular; Mus; Neuraxis; Neuroglia; Oligodendroglia; Oncogenes; Outcome; Pathogenesis; Patients; Pediatric Hospitals; Physicians; Play; Primary Neoplasm; Principal Investigator; RNA Splicing; Regulator Genes; Research Institute; Research Project Grants; Resources; Role; Scientist; Series; System; Testing; The Sun; Translating; Translational Research; Tumor Cell Invasion; Tumor Promotion; Tumor Suppressor Proteins; U251; Variant; Work; career; cell growth; gain of function; glioma cell line; human NFIA protein; improved; in vivo; loss of function; migration; neoplastic cell; neuro-oncology; novel; novel strategies; nuclear factor 1; outcome forecast; overexpression; programs; public health relevance; research study; therapy development; transcription factor; tumor; tumor growth; vector control

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：该提案的重点是核因子IA（NFIA），一种胶质细胞谱系限制性发育调控基因，在胶质瘤发病机制中的潜在作用。NFIA转录因子对于CNS中胶质细胞身份和星形胶质细胞分化的特化是必不可少的。我的初步数据显示，NFIA在人类星形细胞瘤中高度表达，较高的NFIA表达与生存率提高相关。 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，并加速了小鼠脑中U87颅内肿瘤的生长。相反，敲低NFIA（shRNAi）导致软琼脂中的菌落更小，培养物中的细胞生长减少，并抑制小鼠原位U87肿瘤的生长。这些研究结果表明，NFIA在胶质瘤生长中发挥作用，但可能具有不同的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。 我在洛杉矶儿童医院（CHLA）的萨班研究所（SRI）与癌症项目的Anat Erdreich-Epstein和Yves DeClerck博士以及发育生物学项目的大卫沃伯顿博士建立了高度支持的指导关系。此外，我还与加州理工学院的大卫安德森博士建立了密切的合作关系。这一建议得到了导师、部门和机构的全力支持。SRI的全部资源和核心都可用于我的工作。我计划将我职业生涯的重要部分投入到基础和转化研究中，希望将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联合收割机结合起来，以一种新的协同方法寻找神经胶质瘤治疗的新方法。我已经为我目前的研究项目提供了一套有希望的初步数据和具体的实验设计，以及优秀的导师和合作者，这将有助于我成为一名独立的物理学家和科学家的职业目标。 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之间看似不同的关联，但在我的实验系统中加速肿瘤生长，因此将有助于揭示其在人类胶质瘤中的作用及其潜在的分子机制。