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Functional Dissection of the K27M Histone Mutation In Gliomagenesis

胶质瘤发生中 K27M 组蛋白突变的功能剖析

基本信息

批准号：
10581204
负责人：
Oren Josh Becher
金额：
$ 17.69万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10581204
关键词：
Functional Dissection K27M Histone Mutation

项目摘要

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Recently, novel mutations in ACVR1, a BMP pathway receptor, were discovered that commonly co-occur with a K27M mutation in the gene encoding histone H3.1 (H3.1 K27M) in DIPG patient samples. The overall objectives of this proposal are to identify the mechanisms by which mutant ACVR1 and H3.1 K27M contribute to DIPG pathogenesis and to uncover strategies to pharmacologically target these mutations or downstream signaling molecules. Our central hypothesis is that mutant ACVR1 and H3.1 K27M contribute to brainstem gliomagenesis by activating the Stat3 and Notch signaling pathways, respectively. We plan to use novel genetically engineered mouse models representing primary tumors growing in their native microenvironment to interrogate the effects of both mutant ACVR1 and H3.1 K27M on gliomagenesis, proliferation, apoptosis, cell differentiation, self- renewal, cell motility, and angiogenesis in vitro and in vivo. We will also use both genetic and pharmacologic tools to determine the contributions of Stat3 and Notch to ACVR1-mediated functions and to H3.1 K27M-mediated functions, respectively. Finally, we will test a panel of ACVR1, Stat3, and Notch inhibitors in vitro and in vivo in both human and murine DIPG models. Once it is understood how ACVR1 mutations and H3.1 K27M contribute to DIPG pathogenesis, the relevant developmental pathways can be manipulated pharmacologically, resulting in new and innovative therapeutic approaches that are based upon the basic biology inherent, and specific, to DIPG. We anticipate these outcomes will have a positive impact by 1) laying the foundation for future pre-clinical and clinical trials for DIPG, 2) characterizing the first genetically engineered mouse models of DIPG driven by mutant ACVR1 and H3.1 K27M, and 3) advancing our understanding of signaling pathway activities that are essential for DIPG growth.

弥漫性内在脑桥胶质瘤（DIPG）是一种罕见的儿科脑肿瘤，存在有效的疗法。最近，在ACVR1（一种BMP通路受体）中发现了新的突变，通常与编码组蛋白的基因中的K27M突变共同发生 DIPG患者样本中的H3.1（H3.1 K27 M）。本提案的总体目标是确定突变体ACVR1和H3.1 K27 M促进DIPG的机制发病机制，并揭示策略，以靶向这些突变，或下游信号分子。我们的中心假设是突变型ACVR 1和H3.1 K27 M 通过激活Stat3和Notch信号通路促进脑干胶质瘤的发生，分别我们计划使用新的基因工程小鼠模型，肿瘤生长在其天然微环境中，以询问两种突变体 ACVR1和H3.1 K27 M对胶质瘤形成、增殖、凋亡、细胞分化、自更新、细胞运动和血管生成。我们还将使用遗传和用于确定Stat3和Notch对ACVR1介导的功能和H3.1 K27 M介导的功能。最后，我们将测试一组 ACVR1、Stat3和Notch抑制剂在人和鼠DIPG模型中的体外和体内研究。一旦了解ACVR1突变和H3.1 K27 M如何促进DIPG发病机制，相关的发育途径可以被操纵，导致新的和创新的治疗方法是基于固有的基本生物学，具体到DIPG。我们预计这些成果将产生积极的影响，1）奠定为DIPG的未来临床前和临床试验奠定基础，2）表征第一个基因由突变体ACVR 1和H3.1 K27 M驱动的DIPG的工程化小鼠模型，和3）推进我们对DIPG生长所必需的信号通路活动的理解。