Molecular mechanisms mediated by ACVR1 G328V and H3K27M in diffuse intrinsic pontine glioma biology

ACVR1 G328V 和 H3K27M 在弥漫性脑桥胶质瘤生物学中介导的分子机制

• 批准号: 9401637
• 负责人: Flor Maria Mendez
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401637
• 关键词: ACVR1 gene; Abnormal Cell; Address; Affect; Age; Apoptosis; Autopsy; BHLH Protein; Biology; Biopsy; Bone Morphogenetic Proteins; Brain Neoplasms; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Death; Cell Survival; Cells; Child; Childhood Brain Neoplasm; Childhood Brain Stem Neoplasm; Cyclin A; Cyclin-Dependent Kinase Inhibitor; DNA Binding; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; Data; Diagnosis; Diffuse intrinsic pontine glioma; Dominant-Negative Mutation; Down-Regulation; EZH2 gene; Epigenetic Process; Future; Gene Expression; Gene Targeting; Genes; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Genome Stability; Genomics; Genotoxic Stress; Global Change; Goals; Histone H3; Histones; Immunocompetent; Immunohistochemistry; Impairment; In Vitro; Ionizing radiation; Location; Mediating; Methylation; Modality; Modification; Molecular; Mus; Mutation; Nature; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pontine structure; Positioning Attribute; Post-Translational Regulation; Primary Neoplasm; Protein Family; Protein-Serine-Threonine Kinases; Radiation; Recurrence; Reporting; Repression; Role; Signal Pathway; Signal Transduction; Site; Smad Proteins; Tail; Testing; Tissues; Tumor Biology; Variant; Western Blotting; Work; activin A; bone; chemotherapy; common treatment; design; effective therapy; gain of function mutation; helix-loop-helix protein differentiation inhibitor; histone methyltransferase; improved; inhibitor/antagonist; insight; molecular targeted therapies; mouse model; mutant; new therapeutic target; novel; outcome forecast; receptor; repaired; response; targeted treatment; transcription factor; tumor; tumorigenesis

Project Summary/Abstract Diffuse intrinsic pontine glioma (DIPG) is a brain tumor most commonly diagnosed in children of median age 6-7 and the prognosis is very poor. The ten percent survival after two years is less than 2 years. The tumor originates in the pons, but is highly invasive. Due to its sensitive location and invasive nature, the tumor cannot be removed surgically. Chemotherapy and radiation are the only treatment options; however no effective chemotherapy has been found. Thus, studying the intrinsic biology of this tumor is imperative for the design of improved molecularly targeted therapies. This proposal will utilize the information gained from genomic studies of autopsy and biopsy tissue that revealed the presence of recurrent gain of function mutations in ACVR1 and dominant negative K27M mutations in the genes encoding histone H3 variants, H3.3 and H3.1. ACVR1 is a serine-threonine kinase transmembrane signal transduction protein of the bone morphogenetic pathway (BMP); however, it is unknown how altered BMP signaling affects DIPG pathogenesis. The dominant negative mutation occurring in Histone H3.1 and H3.3 variants results in a global loss and redistribution of histone H3K27 tri- methylation which consequently affects gene expression. This proposal will use a genetically engineered immunocompetent mouse model to address the role of ACVR1 G328V and commonly co-expressed H3.1 K27M on DIPG pathogenesis and will seek to understand their impact on the tumor response to DNA damaging agents. In summary, the studies included in this proposal will generate novel translational data relevant to patients with ACVR1 and H3.1 mutations. Our results will aid in the design of future targeted therapies for treatment of DIPG.

项目摘要/摘要 弥漫性桥脑胶质瘤(DIPG)是一种最常被诊断为脑肿瘤的脑肿瘤。 儿童年龄中位数为6-7岁，预后非常差。两年后10%的存活率 两年不到两年。肿瘤起源于脑桥，但侵袭性很强。由于其 由于肿瘤的敏感部位和侵袭性，无法通过手术切除。化疗 和放射治疗是唯一的治疗选择；然而，还没有有效的化疗 找到了。因此，研究该肿瘤的内在生物学特性对于改进设计势在必行。 分子靶向疗法。这项提案将利用从基因组学中获得的信息 对身体解剖和活检组织的研究，发现存在复发性功能增强 组蛋白H3基因ACVR1突变和显性阴性K27M突变 变种，H3.3和H3.1。ACVR1是一种丝氨酸-苏氨酸激酶跨膜信号 骨形态发生途径(BMP)的转导蛋白；然而，它是如何实现的还不清楚 BMP信号改变影响DIPG的发病机制。显性负突变发生在 组蛋白H3.1和H3.3变异导致组蛋白H3K27三重分布的全球丢失和重新分布 甲基化，从而影响基因的表达。这项提议将使用一种基因 ACVR1G328V和ACVR1G328V基因工程免疫小鼠模型 共同在DIPG发病机制上共表达H3.1 K27M，并将寻求了解其 对DNA损伤剂对肿瘤反应的影响。总而言之，这些研究包括在 这项提议将产生与ACVR1和H3.1患者相关的新的翻译数据 突变。我们的研究结果将有助于设计未来治疗DIPG的靶向疗法。