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: 8500476
• 负责人: Hae-Ri Song
• 金额: $ 17.96万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500476
• 关键词: Adult; Agar; Apoptosis; Astrocytes; Astrocytoma; Basic Science; 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; Hospitals; Human; Implant; In Vitro; Institution; Instruction; Intracranial Neoplasms; Knowledge; Link; Los Angeles; Malignant Glioma; Malignant Neoplasms; Mentors; Mining; Molecular; Mus; Neuraxis; Neuroglia; Oligodendroglia; Oncogenes; Outcome; Pathogenesis; Patients; Physicians; Play; Primary Neoplasm; Principal Investigator; RNA Splicing; Regulator Genes; Research Institute; Research Project Grants; Resources; Role; Scientist; Series; System; Testing; The Cancer Genome Atlas; 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; research study; therapy development; transcription factor; tumor; tumor growth; vector control

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.

这一建议的重点是核因子IA （NFIA）的潜在作用，胶质细胞谱系限制