Functional Dissection of the K27M Histone Mutation In Gliomagenesis

弥漫性桥脑胶质瘤(DIPG)是一种少见的儿童脑肿瘤，目前尚无有效的治疗方法或治疗方法。 存在有效的治疗方法。最近，BMP途径受体ACVR1的新突变， 被发现通常与编码组蛋白基因的K27M突变共存 DIPG患者样本中的H3.1(H3.1 K27M)。这项建议的总体目标是 确定ACVR1和H3.1 K27M突变在DIPG中的作用机制 发病机制，并发现针对这些突变或药物的策略 下游的信号分子。我们的中心假设是ACVR1和H3.1 K27M突变株 通过激活STAT3和Notch信号通路促进脑干胶质瘤的发生 分别进行了分析。我们计划使用新的基因工程小鼠模型来代表主要的 肿瘤在其自然微环境中生长以询问这两个突变体的影响 ACVR1和H3.1 K27M对胶质瘤发生、增殖、凋亡、细胞分化、自身 体外和体内的更新、细胞运动和血管生成。我们还将同时使用Genetic和 确定STAT3和Notch在ACVR1介导中的作用的药理学工具 功能和H3.1 K27M介导的功能。最后，我们将测试一组 ACVR1、STAT3和Notch抑制剂在人体和小鼠DIPG模型中的体外和体内研究。 一旦了解了ACVR1突变和H3.1 K27M在DIPG发病机制中的作用， 相关的发育途径可以在药理学上进行操纵，从而产生新的 和创新的治疗方法，基于基本的生物学固有的，和 具体到DIPG。我们预计这些结果将产生积极影响，1)为 DIPG未来临床前和临床试验的基础，2)第一个遗传学特征 突变ACVR1和H3.1 K27M驱动的DIPG工程化小鼠模型；3)进展 我们对DIPG生长所必需的信号通路活动的理解。

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.