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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的永久性嗅觉丧失是与感觉神经母细胞瘤 (ENB) 相关的一种常见疾病，这种肿瘤被认为是起源于鼻子的嗅上皮。这是因为无论情况如何，都需要进行大量手术切除肿瘤级别。因此，有必要开发新的医疗策略来保护嗅觉在这个患者群体中。嗅觉上皮是一个神经源性生态位，可产生神经元并支持上皮细胞的整个生命周期，以及正常上皮增殖的各个未分化阶段在 ENB 中观察到了发展。表观遗传调节因子多梳抑制复合物 2 (PRC2) 参与驱动全身干细胞生态位的增殖细胞状态。我们已经证明 PRC2 对于嗅上皮基底细胞增殖至关重要，我们已经确定它在 ENB 中的增殖细胞。由于 ENB 是一种罕见肿瘤，机制生物学研究很少，也没有细胞存在线或鼠标模型。此外，大多数 ENB 不具有共同的驱动突变，强调表观遗传调控的重要性。在这里我建议利用新开发的多组学研究调查 PRC2 在人 ENB 中的表达如何指定细胞状态并促进肿瘤生长。我将对多个肿瘤进行单细胞染色质和转录组分析，以确定以下区域染色体的可及性。此外，我将在人类 ENB 样本中使用药理学测定来评估对转录的下游影响。最后，空间转录组学将用于定义 ENB 细胞和分子组成，包括 PRC 相关表达，以及与正常嗅觉的比较上皮细胞，阐明 ENB 内肿瘤细胞和免疫细胞之间的细胞信号传导动态微环境。拟议研究的完成将确定 ENB 与目标是确定新的可药物靶点，从而提高存活率并保留气味。共，本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将为我提供必要的严格培训，以帮助我成为一名成功的外科医生兼科学家。鼻科和前颅底手术。