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胶质瘤发生中的作用

基本信息

批准号：
10675589
负责人：
Maya Srikanth Graham
金额：
$ 19.55万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675589
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 Cell Separation 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 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 Phenotype Population Positioning Attribute Pre-Clinical Model Qualifying Regulation Research Research Personnel Resolution Resources Role Side Signal Transduction System TP53 gene Techniques Therapeutic Training Transgenes Transgenic Mice Transgenic Organisms Translating Variant Work career career development childhood cancer mortality chromatin remodeling constitutive expression effective therapy epigenetic regulation experience gene induction human stem cells in vivo induced pluripotent stem cell inhibitor innovation insight instructor mutant nerve stem cell neural neuro-oncology neurodevelopment novel oncohistone pharmacologic pre-clinical programs promoter screening single-cell RNA sequencing skills targeted treatment therapeutic development therapeutic target transcriptome sequencing transgene expression translational oncology tumor tumor initiation

项目摘要

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.

项目概要该提案的总体目标是定义表观遗传学和发育背景的相互作用驱动儿科高级神经胶质瘤（pHGG），这是由组蛋白突变定义的普遍致命的肿瘤，以便这项工作利用了一种创新的基于大脑类器官的模型，该模型允许癌组蛋白突变体和三组中癌基因表达的动态调节的并排比较利用这一创新模型，格雷厄姆博士将使用尖端的单细胞。分析技术和临床前神经胶质瘤建模，以解决目前阻碍的未解答的问题在目标 1 中，将开发染色质分析和单细胞 RNA 测序。用于研究两种不同的癌组蛋白（H3.3K27M 和 H3.3G34V）在神经过程中的不同作用在目标 2 中，将操纵突变的时间和顺序来评估细胞的影响。最后，在目标 3 中，正交遗传“拯救”和药理学。抑制方法将用于探究这些突变在肿瘤维持中的作用。这项工作以及 Graham 博士的职业目标与 NINDS 的使命非常一致，即寻求基本的有关大脑的知识，并通过拟议的研究将这些知识转化为临床影响。以及伴随的职业发展计划，格雷厄姆博士将获得表观遗传学方面的必要培训， Graham 博士是生物信息学和临床前神经胶质瘤研究的讲师。纪念斯隆凯特琳癌症中心 Ingo Mellinghoff 博士指导下的神经肿瘤学 (MSK) 梅林霍夫博士是转化神经胶质瘤研究领域的领导者，拥有良好的指导记录。他和格雷厄姆博士组建了一个杰出的咨询委员会，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 Levine 和 Nicholas Socci 博士为培养崭露头角的职业生涯提供了优越的环境。生物医学研究，拥有无与伦比的资源、支持和合作机会。完成拟议的工作后，格雷厄姆博士将处于理想的位置并具有独特的资格来从事以下职业：独立研究者阐明神经谱系表观遗传调控的基本方面承诺并应用她的发现来解决恶性胶质瘤治疗中未满足的需求。