课题基金 / 基金详情

Modeling pediatric glioma in human ES cells:mechanistic and therapeutic insights

Modeling pediatric glioma in human ES cells:mechanistic and therapeutic insights
在人类 ES 细胞中模拟儿科神经胶质瘤:机制和治疗见解
批准号:
9317449
负责人:
VIVIANE TABAR
金额:
$39.24万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-18 至 2021-06-30

项目摘要

项目成果

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中文摘要
翻译
摘要/项目摘要 DIPGs是儿童时期迅速致死的脑瘤。大多数患者在一年内死亡 一年或两年的诊断,因为没有有效的治疗这种毁灭性的疾病。他们的 脑干的关键位置长期以来一直禁止接触肿瘤组织。最近, 测序研究揭示了由单一氨基酸组成的新的组蛋白突变 组蛋白H3变异体尾部的替换。排他性地同时出现的模式 具有特定信号通路改变的组蛋白突变以及发病年龄和脑 出现了地区变化。利用这些数据和严格的开发 肿瘤之窗,我们的团队已经建立了第一个有效的基因工程 基于人类ES细胞的肿瘤模型。该模型产生的肿瘤重现了 疾病的遗传、转录体、表观遗传学和组织学特征,从而提供 这是研究这种疾病的宝贵工具。全基因组研究表明,组蛋白 突变导致细胞的发育状态重置为更早、更原始的状态 干细胞状态。 重要的是,我们的建模系统是药物筛选的有效平台, 导致鉴定出一个新的蛋白质-蛋白质相互作用网络作为关键成分 这些肿瘤的增殖和生长机制,以蛋白质脑膜为中心。 Menin是一种有多个伙伴的独特蛋白质;它在MLL的背景下是致癌的 重新排列的白血病。我们的数据显示,使脑膜素沉默或抑制其MLL与 Menin抑制剂导致细胞增殖减少和细胞死亡增加,这是一种全新的 在胶质瘤中从未报道过这一发现,这增加了治疗策略的希望。 该提案旨在通过构建新的模型来扩展我们的HES建模平台 代表了脑干中所描述的体细胞突变的遗传多样性 神经胶质瘤。我们还将研究组蛋白突变下游的事件,重点是 薄荷素致癌作用的分子基础。最终目标是开发一种治疗方法 DIPGs的战略,利用新合成的薄荷素抑制剂。 我们的研究也应该有助于将HES细胞发展成更广泛的适用范围 利用它们的许多优势建立癌症模型的平台,包括访问 无限量供应适合阶段的人体细胞用于机械或治疗研究, 能够从肿瘤的起始阶段到肿瘤的维持阶段研究肿瘤生物学,以及 实施复杂的基因工具。
英文摘要
Abstract / Project Summary DIPGs are rapidly lethal brain tumors of childhood. The majority of patients die within a year or two of diagnosis, as there is no effective treatment for this devastating disease. Their critical location in the brainstem has long prohibited access to tumor tissue. Recently, sequencing studies revealed novel histone mutations consisting of single amino acid substitutions in the tail of the histone H3 variants. A pattern of exclusive co-occurrence of histone mutations with specific signaling pathway alterations as well as age of onset and brain region alterations emerged. Taking advantage of these data and of the strict developmental window of the tumors, our team has built what is effectively the first genetically-engineered human ES cell-based model of a tumor. The model yielded tumors that recapitulated the genetic, transcriptomal, epigenetic and histological features of the disease, thus providing valuable tools for the study of the disease. Genome wide studies suggested that the histone mutation led to a resetting of the developmental status of the cells to an earlier more primitive stem cell state. Importantly, our modeling system served as an effective platform for drug screens, leading to the identification of a novel protein –protein interaction network as a key component of the proliferative and growth machinery of these tumors, centered on the protein menin. Menin is a unique protein with multiple partners; it is oncogenic in the context of the MLL rearranged leukemias. Our data show that silencing menin or inhibiting its MLL interaction with a menin inhibitor leads to a decrease in proliferation and increased cell death, a completely novel finding never reported in glioma, that raises the promise of a therapeutic strategy. The proposal aims to expand our hES modeling platform by building new models that are representative of the genetic diversity of the somatic mutations described in brainstem gliomas. We will also study the events downstream of the histone mutations, with emphasis on the molecular basis of the oncogenic role of menin. The ultimate goal is to develop a therapeutic strategy for DIPGs, taking advantage of newly synthesized menin inhibitors. Our studies should also contribute to developing hES cells into a more widely applicable platform for cancer modeling capitalizing on their many advantages, including access to an unlimited supply of stage appropriate human cells for mechanistic or therapeutic studies, the ability to study tumor biology from the step of initiation to tumor maintenance, and the ease of implementing sophisticated genetic tools.
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