Transcriptional control of Glioma development

神经胶质瘤发育的转录控制

• 批准号: 9517217
• 负责人: Nadia Dahmane
• 金额: $ 37.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-28 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9517217
• 关键词: Address; Adult; Adverse effects; Affect; Alpha Cell; Biological Models; Brain; Brain Neoplasms; Cell Culture Techniques; Cell physiology; Cells; Clinical; Complementary DNA; Computer Analysis; Data; Data Analyses; Detection; Development; Event; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Glioblastoma; Glioma; Goals; Growth; Growth Inhibitors; Human; In Vitro; Intervention; Knockout Mice; Link; Longevity; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Molecular; Molecular Target; Mus; NF1 gene; Nature; Neuronal Differentiation; Neurons; Other Genetics; Pathway interactions; Patients; Phenotype; Play; Process; Property; Radio; Recurrence; Regulation; Resistance; Role; Snails; Stem cells; Survival Rate; TP53 gene; Testing; Therapeutic Intervention; Tissues; Transcription Repressor/Corepressor; Transcriptional Regulation; Tumorigenicity; Xenograft Model; Xenograft procedure; brain cell; design; experimental study; gene function; genetic signature; glioma cell line; in vivo; innovation; migration; molecular subtypes; mouse model; nerve stem cell; novel; outcome forecast; prevent; progenitor; public health relevance; relating to nervous system; self-renewal; slug; small hairpin RNA; stem; stemness; targeted treatment; transcription factor; tumor; tumor growth; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): Gliomas are highly heterogeneous, incurable adult brain tumors. They are classified in various grades depending on their aggressiveness, with glioblastoma (GBM) being extremely invasive with an average patient life span of about one year after detection. GBMs can either arise de novo (primary GBM) or derive from low-grade glioma progression (secondary GBM). The mechanisms leading to progression of low-grade gliomas to GBM are still poorly understood. In addition, the failure of existing therapies may be due to the existence of glioma stem cells (GSCs) that are tumorigenic, radio- and chemo-resistant and capable of inducing recurrence. Our major goal is to elucidate the mechanisms that regulate glioma progression, especially those pathways required for cell self-renewal and invasion. Gene transcriptional profiling of high-grade gliomas has identified distinct molecular subtypes, including a "mesenchymal" subtype that consists of invasive tumors with a poor prognosis. We have shown that RP58 (ZNF238, ZFP238) acts as a tumor growth inhibitor in glioma cell lines. RP58 is a transcription factor required for brain development and neuronal differentiation. In addition, our preliminary data indicate that the reduction of RP58 expression correlates with increased glioma aggressiveness, including acquisition of a mesenchymal phenotype. Our overall hypothesis is that RP58 acts to inhibit glioma growth, stemness and invasion in part by repressing a mesenchymal gene signature, and that loss of RP58 is a critical event in glioma formation and/or progression and will be addressed with the following aims: Aim1: Determine the function of RP58 in glioma stem cells. This aim will test the role of RP58 in glioma growth and invasion in vitro using primary glioma stem cell cultures and in vivo using orthotopic xenografts of glioma stem cells in mice. Aim2: Determine whether loss or reduced RP58 expression in mice contributes to brain tumor formation and/or invasion. Using genetic mouse models, we will test the hypothesis that reduction or deletion of Rp58 is sufficient for glioma formation and/or invasion in mice. Aim 3. Determine the mechanisms involved in RP58 function to antagonize GSC self-renewal and/or glioma invasiveness? In this aim we will decipher the molecular mechanisms required for RP58 to regulate the self-renewal capacity of normal and cancer progenitors, its function in regulating mesenchymal properties in brain cells, and how these two processes are linked in gliomas. This project will address key aspects of glioma stemness, and aggressiveness, with a focus on a novel regulator of glioma progression. Completion of this project will identify novel mechanisms underlying glioma development and identify alternative targets for therapeutic intervention.

 描述（由申请人提供）：神经胶质瘤是高度异质性、不可治愈的成人脑肿瘤。它们根据其侵袭性分为不同的等级，胶质母细胞瘤（GBM）具有极强的侵袭性，检测后平均患者寿命约为一年。GBM可以从头产生（原发性GBM）或源自低级胶质瘤进展（继发性GBM）。导致低级别胶质瘤进展为GBM的机制仍然知之甚少。此外，现有疗法的失败可能是由于胶质瘤干细胞（GSC）的存在，这些干细胞具有致瘤性、放射性和化学抗性，并且能够诱导复发。我们的主要目标是阐明调节胶质瘤进展的机制，特别是那些细胞自我更新和侵袭所需的途径。高级别胶质瘤的基因转录谱已经确定了不同的分子亚型，包括由预后不良的侵袭性肿瘤组成的“间质”亚型。我们已经证明RP 58（ZNF 238，ZFP 238）在胶质瘤细胞系中作为肿瘤生长抑制剂。RP 58是脑发育和神经元分化所需的转录因子。此外，我们的初步数据表明RP 58表达的减少与胶质瘤侵袭性的增加相关，包括获得间充质表型。我们的总体假设是，RP 58的行为，以抑制胶质瘤的生长，干细胞和入侵部分通过抑制间充质基因签名，和RP 58的损失是一个关键的事件在胶质瘤的形成和/或进展，并将解决以下目标：目标1：确定RP 58在胶质瘤干细胞的功能。该目的将使用原代胶质瘤干细胞培养物在体外和使用小鼠中胶质瘤干细胞的原位异种移植物在体内测试RP 58在胶质瘤生长和侵袭中的作用。目的2：确定小鼠中RP 58表达的丧失或降低是否有助于脑肿瘤形成和/或侵袭。使用遗传小鼠模型，我们将测试的假设，减少或删除Rp 58是足够的胶质瘤形成和/或侵袭小鼠。目标3.确定RP 58拮抗GSC自我更新和/或胶质瘤侵袭的机制？在这个目标中，我们将破译RP 58调节正常和癌症祖细胞自我更新能力所需的分子机制，其在调节脑细胞间充质特性中的功能，以及这两个过程在胶质瘤中是如何联系在一起的。该项目将解决神经胶质瘤的干性和侵袭性的关键方面，重点是神经胶质瘤进展的新调节剂。该项目的完成将确定神经胶质瘤发展的新机制，并确定治疗干预的替代靶点。