NORMAL & NEOPLASTIC GROWTH IN THE BRAIN

普通的

• 批准号: 10270671
• 负责人: SUZANNE J BAKER
• 金额: $ 188.48万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270671
• 关键词: ACVR1 gene; Address; Antibody-drug conjugates; Automobile Driving; Basic Science; Biological Models; Biometry; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Etiology; Cell Lineage; Cell membrane; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical Trials; Collaborations; Competence; Complex; Data; Dependence; Development; Developmental Process; Diffuse intrinsic pontine glioma; Disease; Drug Combinations; Epigenetic Process; Experimental Designs; FDA approved; FRAP1 gene; Functional disorder; Funding; Genes; Genetic Transcription; Goals; Growth; H3 K27M mutation; Heterogeneity; Immunotherapy; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Methyltransferase; Molecular; Morbidity - disease rate; Mutate; Mutation; Neoplasms; Paper; Pathogenesis; Pathway interactions; Pediatric Neoplasm; Pharmaceutical Preparations; Phenotype; Play; Preclinical Testing; Predisposition; Proteome; Publishing; Regulation; Research Personnel; Resources; Role; SHH gene; SMYD3 gene; Seminal; Series; Solid; Source; Study models; Susceptibility Gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Translating; Translations; Tumor Subtype; Variant; Work; antibody test; base; biological adaptation to stress; cancer predisposition; childhood cancer mortality; data integration; drug testing; epigenome; experience; experimental study; hindbrain; human disease; improved; inhibitor/antagonist; insight; loss of function; mTOR inhibition; medulloblastoma; member; mortality; next generation sequence data; novel; novel therapeutics; oligodendrocyte lineage; patient derived xenograft model; programs; response; spatiotemporal; success; therapeutic evaluation; therapeutic target; transcriptome; translational impact; treatment response; tumor; tumor initiation; tumorigenesis

Overall Program Summary Brain tumors are the most common pediatric solid malignancies, and the leading cause of cancer-related death in children. The long-term goal of this Program Project is to improve understanding and treatment of diffuse intrinsic pontine glioma (DIPG) and medulloblastoma (MB), which cause devastating mortality and morbidity in children. Over the last funding period, P01 investigators Baker, Roussel and Gilbertson demonstrated important contributions of epigenetic dysregulation in DIPG and MB, a role for pediatric brain tumor mutations in stress response, and therapeutic vulnerabilities in MB subtypes. P01 Investigator Northcott joins as a new Project leader with a proposal based on the discovery of a new MB cancer predisposition gene. This highly interactive team proposes an integrated series of experiments to leverage recent progress and the most advanced techniques to investigate aberrant cell fate/cell state regulation, to determine the contribution of epigenome, transcriptome and proteome dysregulation to disrupted development and tumorigenesis, and to identify developmental and epigenetic functional dependencies and test therapeutic vulnerabilities of pediatric hindbrain tumors. In Project 1, S Baker is focused on the contribution of H3K27M mutations in disrupted development, tumor initiation and spatiotemporal selectivity of tumorigenesis, and how cooperative contributions of ACVR1 and PI3K/mTOR pathways influence heterogeneity of therapeutic response to selective inhibitors. In Project 2, M Roussel investigates the role of the methyltransferase SMYD3, and tests drug combinations that enhance efficacy of methyltransferase inhibitors in the Group 3 MB subtype. In Project 3, P Northcott evaluates how loss of function in ELP1 drives MB predisposition, perturbs regulation of translation elongation, and cooperates with other mutations in the SHH-MB subtype. In Project 4, R Gilbertson investigates how DDX3X mutations disrupt cell fate decisions, transcription and translation regulation, and investigates novel therapies to exploit the defective blood-brain-barrier in WNT-MB. All four projects rely on the outstanding expertise in Core B, where all next-generation sequence data will be analyzed including integrated cross-comparison of data from multiple projects, and rigorous biostatistical approaches will be applied for experimental design and interpretation. Core C is integral to all projects and will provide expert neuropathological review of all tumor models studied in the program to assess their similarity and relevance to primary human disease and will assist with phenotype analyses and optimizing immunohistochemical analyses. The collective efforts of the Program will impact our understanding of disease pathogenesis of DIPG and MB, extend beyond pediatric hindbrain tumors, to enhance understanding of how aberrant regulation of the epigenome, transcriptome and proteome disrupt normal development and contribute to cancer. Our success is guaranteed by our strong track record of productive collaborations, the unique resources and the outstanding Cores to facilitate the acquisition, exchange, and integration of data.

总体计划摘要 脑肿瘤是最常见的小儿固体恶性肿瘤，也是癌症相关死亡的主要原因 在儿童中。该计划项目的长期目标是提高对分散的理解和治疗 固有的庞然大拉神经胶质瘤（DIPG）和髓母细胞瘤（MB），它们在死亡率和发病率中引起毁灭性的死亡率和发病率 孩子们。在上一个资金期间，P01调查人员贝克，鲁塞尔和吉尔伯逊证明了重要 DIPG和MB表观遗传失调的贡献，这是小儿脑肿瘤突变的作用 MB亚型的反应和治疗漏洞。 P01调查员诺斯科特（Northcott）加入了一个新项目 基于发现新的MB癌症易感基因的提案的领导者。这种高度互动 团队提出了一系列集成的实验，以利用最近的进步和最先进的 研究异常细胞命运/细胞状态调节的技术，以确定表观基因组的贡献， 转录组和蛋白质组失调会破坏发育和肿瘤发生，并确定 儿科后脑的发育和表观遗传依赖性以及测试治疗脆弱性 肿瘤。在项目1中，S Baker专注于H3K27M突变在破坏的发展中的贡献， 肿瘤起始和肿瘤发生的时空选择性以及ACVR1的合作贡献如何 PI3K/MTOR途径影响选择性抑制剂的治疗反应的异质性。在项目2中 M Roussel研究了甲基转移酶SMYD3的作用，并测试了增强的药物组合 3 MB亚型中甲基转移酶抑制剂的功效。在项目3中，P Northcott评估了如何损失 ELP1中的功能驱动MB倾向，翻译伸长的调节，并与 SHH-MB亚型中的其他突变。在项目4中，R Gilbertson研究了DDX3X突变如何破坏 细胞命运的决定，转录和翻译调节，并研究了新型疗法以利用 Wnt-MB中的血脑障碍有缺陷。这四个项目都依赖于核心B中的出色专业知识， 将分析下一代序列数据，包括来自多个数据的数据的集成交叉比较 项目和严格的生物统计方法将用于实验设计和解释。核 C是所有项目不可或缺的一部分，并将提供专家神经病理学评论 评估其与原发性疾病的相似性和相关性的计划，并将有助于表型 分析和优化免疫组织化学分析。该计划的集体努力将影响我们的 了解DIPG和MB的疾病发病机理，延伸到小儿后脑肿瘤，以增强 了解表观基因组，转录组和蛋白质组的异常调节如何破坏正常 发展并促进癌症。我们的富有生产力记录可以保证我们的成功 合作，独特的资源和杰出的核心，以促进收购，交流和 数据集成。