Leveraging multi-omics to define the role of epigenetic regulation by PRC2 in Esthesioneuroblastoma

利用多组学确定 PRC2 在视神经母细胞瘤中的表观遗传调控作用

• 批准号: 10748697
• 负责人: John Barratt Finlay
• 金额: $ 5.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748697
• 关键词: ATAC-seq; Adjuvant; Anosmia; Anterior; Area; Automobile Driving; Basal Cell; Biological; Biological Assay; Brain; COVID-19 associated anosmia; Cell Differentiation process; Cell Line; Cell Proliferation; Cell physiology; Cells; Chemotherapy and/or radiation; Chromatin; Collection; Complex; Custom; Data; Data Set; Development; Disease; Epigenetic Process; Epithelial Cells; Epithelium; Excision; Fossa; Genes; Genetic Transcription; Goals; Growth; Human; Immune; Immunotherapy; Invaded; Life; Lymphocyte; Lymphocytic Infiltrate; Maintenance; Malignant Neoplasms; Maps; Medical; Mentorship; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Nasal cavity; Neoadjuvant Therapy; Neuronal Differentiation; Neurons; Nose; Ocular orbit; Olfactory Epithelial Cell; Olfactory Epithelium; Operative Surgical Procedures; Organ; Outcome; Paraffin Embedding; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Play; Polycomb; Population; Process; Proliferating; Proliferation Marker; Proteins; Proteomics; Publishing; Recurrence; Research; Resected; Resolution; Role; Sampling; Scientist; Signal Transduction; Smell Perception; Spatial Distribution; Specific qualifier value; Specimen; Stains; Surgeon; Techniques; Technology; Therapeutic; Tissue Embedding; Training; Tumor Promotion; Tumor Tissue; Tumor-Derived; Undifferentiated; Up-Regulation; Variant; Work; age related; biocomputing; cancer type; career; cell type; driver mutation; epigenetic regulation; human tissue; improved; inhibitor; insight; mouse model; multiple omics; nano-string; neurogenesis; new therapeutic target; novel; novel therapeutics; olfactory neurogenesis; patient population; pharmacologic; post-COVID-19; preservation; progenitor; rare cancer; skull base; stem cell niche; stem cells; transcriptome sequencing; transcriptomic profiling; transcriptomics; treatment strategy; tumor; tumor growth

ABSTRACT Permanent smell loss is a common morbidity associated with esthesioneuroblastoma (ENB), a tumor thought to arise from the olfactory epithelium in the nose. This is due to necessity for bulk surgical resection, regardless of tumor grade. As such, the development of novel medical treatment strategies is necessary to preserve olfaction in this patient population. The olfactory epithelium is a neurogenic niche that produces neurons and supporting epithelial cells throughout life, and various undifferentiated stages of normal epithelial proliferation and development have been observed in ENB. The epigenetic regulator polycomb repressive complex 2 (PRC2) has been implicated in driving proliferative cell states in stem cell niches throughout the body. We have shown that PRC2 is crucial for basal cell proliferation in the olfactory epithelium, and we have identified that it is expressed in proliferating cells in ENB. Because ENB is a rare tumor, mechanistic biological studies are sparse, and no cell lines or mouse models exist. Furthermore, the majority of ENBs do not share common driver mutations, emphasizing the importance of epigenetic regulation. Here I propose to utilize newly-developed multi-omic studies to investigate how PRC2 expression in human ENB specifies cellular states and contributes to tumor growth. I will perform single cell chromatin and transcriptomic assays on multiple tumors to identify areas of chromosomal accessibility. Furthermore, I will use pharmacologic assays in human ENB samples to assess the downstream effects on transcription. Finally, spatial transcriptomics will be used to define ENB cellular and molecular composition, including PRC-associated expression, and how this compares to normal olfactory epithelium, to elucidate cellular signaling dynamics among tumor and immune cells within the ENB microenvironment. Completion of the proposed studies will define epigenetic drivers co-opted by ENB with the goal of identifying new druggable targets, allowing for improved survival and preservation of smell. Altogether, the research and training plan outlined in this proposal combined with expert mentorship from Dr. Bradley Goldstein will prepare me with the rigorous training necessary for a successful career as a surgeon-scientist in rhinology and anterior skull base surgery.

抽象的 永久气味丧失是与雌激素细胞瘤（ENB）相关的常见发病率，这是一种被认为是肿瘤 来自鼻子中的嗅觉上皮。这是由于必须进行批量手术切除的必要 肿瘤等级。因此，必须制定新型医疗策略以保存嗅觉 在这个患者人群中。嗅觉上皮是一种神经源性的生态位，产生神经元和支持 一生的上皮细胞，以及正常上皮增殖的各种未分化阶段 在ENB中观察到了发展。表观遗传调节剂Polycomb抑制性复合物2（PRC2）具有 与驱动整个体内干细胞壁细胞中的增殖细胞态有关。我们已经表明 PRC2对于嗅觉上皮中的基底细胞增殖至关重要，我们已经确定它是表达的 在ENB中的增殖细胞中。因为ENB是一种罕见的肿瘤，所以机械生物学研究很少，没有细胞 线路或鼠标模型存在。此外，大多数ENB不共享常见的驾驶员突变， 强调表观遗传调节的重要性。在这里，我建议利用新开发的多摩变 研究人类ENB中PRC2表达如何指定细胞状态并有助于肿瘤的研究 生长。我将对多个肿瘤进行单细胞染色质和转录组分析，以识别 染色体可及性。此外，我将在人类ENB样品中使用药理学测定来评估 下游对转录的影响。最后，空间转录组学将用于定义ENB细胞和 分子组成，包括与PRC相关的表达，以及与正常嗅觉相比 上皮，以阐明ENB内肿瘤和免疫细胞之间的细胞信号传导动力学 微环境。拟议研究的完成将定义由ENB选择的表观遗传驱动因素 确定新型可毒靶的目标，以改善生存和闻到的气味。共， 该提案中概述的研究和培训计划与布拉德利博士的专家指导相结合 戈德斯坦（Goldstein）将为我做好为成功职业生涯所必需的严格培训做好准备的 鼻科和前颅底手术。