Defining the role of developmental context in oncohistone-driven gliomagenesis

定义发育背景在肿瘤组蛋白驱动的神经胶质瘤发生中的作用

• 批准号: 10507387
• 负责人: Maya Srikanth Graham
• 金额: $ 19.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507387
• 关键词: 3-Dimensional; Address; Adult; Advisory Committees; Area; Automobile Driving; Bioinformatics; Biological Models; Biology; Biomedical Research; Brain; Brain Neoplasms; Cancer Etiology; Cell Lineage; Cells; Cerebrum; Childhood Glioma; Chromatin; Chronology; Clinical; Clinical Trials; Collaborations; Competence; DNA methylation profiling; Data; Development; Development Plans; Dominant-Negative Mutation; Doxycycline; Engineering; Environment; Epigenetic Process; Event; Foundations; Genetic; Glioma; Gliomagenesis; Goals; Histology; Histone H3; Histones; Human; In Vitro; Knowledge; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Glioma; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Mesenchymal; Mission; Modeling; Molecular; Mutation; National Institute of Neurological Disorders and Stroke; Neurons; Oncogenes; Organoids; PDGFRA gene; Pathogenesis; Patients; Pharmacology; Phenotype; Population; Positioning Attribute; Pre-Clinical Model; Regulation; Research; Research Personnel; Resolution; Resources; Role; Side; Signal Transduction; System; TP53 gene; Techniques; Therapeutic; Training; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Variant; Work; base; career; career development; childhood cancer mortality; chromatin remodeling; effective therapy; epigenetic regulation; experience; human stem cells; in vivo; induced pluripotent stem cell; inhibitor; innovation; insight; instructor; mutant; nerve stem cell; neuro-oncology; neurodevelopment; novel; oncohistone; pre-clinical; programs; promoter; relating to nervous system; screening; single-cell RNA sequencing; targeted treatment; therapeutic development; therapeutic target; transcriptome sequencing; transgene expression; translational oncology; tumor; tumor initiation

Project Summary The overarching goal of this proposal is to define the interplay of epigenetics and developmental context in driving pediatric high-grade gliomas (pHGG), universally lethal tumors defined by histone mutations, so as to identify better targeted treatments. This work utilizes an innovative cerebral organoid-based model that allows side-by-side comparison of oncohistone mutants and dynamic modulation of oncogene expression in a three- dimensional human context. Leveraging this innovative model, Dr. Graham will use cutting-edge single cell profiling techniques and preclinical glioma modeling to address unanswered questions that currently hamper therapeutic development for these patients. In Aim 1, chromatin profiling and single cell RNA sequencing will be used to investigate the distinct effects of two different oncohistones (H3.3K27M and H3.3G34V) during neural development. In Aim 2, the timing and order of mutations will be manipulated to evaluate the impact of cellular and mutational context on tumor phenotype. Finally, in Aim 3, orthogonal genetic “rescue” and pharmacologic inhibition approaches will be used to interrogate the role of these mutations in tumor maintenance. This work, as well as Dr. Graham's career goal, is well-aligned with the NINDS mission to seek basic knowledge about the brain and to translate that knowledge into clinical impact. Through the proposed studies and the accompanying career development plan, Dr. Graham will gain essential training in epigenetics, bioinformatics and preclinical glioma studies, critical gaps in her current skillset. Dr. Graham is an Instructor of Neuro-Oncology under the mentorship of Dr. Ingo Mellinghoff at Memorial Sloan Kettering Cancer Center (MSK). Dr. Mellinghoff is a leader in translational glioma research with a strong track record of mentoring trainees to independence. He and Dr. Graham have assembled an exceptional Advisory Committee with expertise in chromatin biology, translational oncology, and bioinformatic analyses: Dr. Kristian Helin, Dr. Ross Levine and Dr. Nicholas Socci. MSK provides an outstanding environment for cultivating budding careers in biomedical research, with unparalleled resources, support, and opportunities for collaboration. Upon completion of the proposed work, Dr. Graham will be ideally positioned and uniquely qualified for a career as an independent investigator elucidating fundamental aspects of epigenetic regulation in neural lineage commitment and applying her findings to address the unmet needs in the treatment of malignant glioma.

项目摘要 该提案的总体目标是确定表观遗传学和发育背景的相互作用， 驱动儿科高级别胶质瘤（pHGG），普遍致命的肿瘤定义的组蛋白突变，以便 更好的针对性治疗。这项工作利用了一种创新的基于脑类器官的模型， 并排比较癌组蛋白突变体和癌基因表达的动态调节， 多维人文背景利用这种创新模式，Graham博士将使用尖端的单细胞 分析技术和临床前胶质瘤建模，以解决目前阻碍 为这些患者提供治疗。在目标1中，染色质分析和单细胞RNA测序将 研究两种不同的癌组蛋白（H3.3K27M和H3.3G34V）在神经细胞凋亡过程中的不同作用。 发展在目标2中，将操纵突变的时间和顺序，以评估细胞免疫的影响。 和肿瘤表型的突变背景。最后，在目标3中，正交遗传“拯救”和药理学 将使用抑制方法来研究这些突变在肿瘤维持中的作用。 这项工作，以及格雷厄姆博士的职业目标，是与NINDS的使命，以寻求基本的 关于大脑的知识，并将这些知识转化为临床影响。通过拟议的研究 以及随之而来的职业发展计划，格雷厄姆博士将获得表观遗传学的基本培训， 生物信息学和临床前胶质瘤研究，她目前的技能的关键差距。格雷厄姆博士是一名教师， 在纪念斯隆凯特琳癌症中心Ingo Mellinghoff博士的指导下，神经肿瘤学 （MSK）。Mellinghoff博士是转化胶质瘤研究的领导者， 实习生独立他和格雷厄姆博士组建了一个特殊的咨询委员会， 染色质生物学、转化肿瘤学和生物信息学分析方面的专业知识：Kristian Helin博士、Ross博士 莱文和尼古拉斯·索奇博士。MSK提供了一个优秀的环境，培养萌芽的职业生涯， 生物医学研究，拥有无与伦比的资源，支持和合作机会。后 完成拟议的工作，格雷厄姆博士将是理想的定位和独特的职业资格， 一个独立的研究者阐明神经谱系中表观遗传调控的基本方面 承诺和应用她的研究结果，以解决在恶性胶质瘤的治疗未得到满足的需求。