Genomics Core

基因组学核心

• 批准号: 10470363
• 负责人: Jaroslav Jelinek
• 金额: $ 23.11万
• 依托单位: CORIELL INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470363
• 关键词: Bioinformatics; CDK4 gene; CDK9 Protein Kinase; Cells; Cessation of life; ChIP-seq; Chromatin; Clinical; Clinical Research; Clinical Trials; Collection; Complex; Cyclin-Dependent Kinases; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Modification Methylases; DNA Sequence Alteration; DNA methyltransferase inhibition; Data; Data Analyses; Dimensions; EZH2 gene; Endogenous Retroviruses; Epigenetic Process; Equipment; Gene Expression; Gene Mutation; Genetic Transcription; Genomics; Goals; Human Resources; Immune; Immune checkpoint inhibitor; Immunization; Immunotherapy; Inflammasome; Intervention; Methylation; Mutation Detection; Pathology; Polycomb; Population; Pre-Clinical Model; Principal Investigator; Quality Control; Repetitive Sequence; Research Project Grants; Resources; Sampling; Signal Transduction; Solid Neoplasm; Statistical Data Interpretation; T-Lymphocyte; Therapeutic; Tissues; Translational Research; Tumor Tissue; Tumor-infiltrating immune cells; biobank; cancer cell; cancer therapy; data acquisition; data management; data sharing; design; epigenetic therapy; epigenomics; exhaustion; exome sequencing; experimental study; genome-wide; high dimensionality; high throughput analysis; inhibitor; innovation; machine learning algorithm; novel therapeutic intervention; preclinical study; predicting response; prospective; single-cell RNA sequencing; synergism; targeted treatment; transcriptome sequencing; transcriptomics; translational study; tumor

Abstract - Genomics, Epigenomics and Bioinformatics Core The Genomics, Epigenomics, and Bioinformatics Core will provide personnel, equipment, and expertise to support all projects of the Epigenetic Therapy SPORE. The Core will be a resource for design and execution of genomic and epigenomic experiments, data acquisition, quality control, bioinformatic analysis, data management, sharing and distribution. It will closely cooperate with all SPORE Projects and the Pathology/Biospecimen Core. Project 1 studies immune-sensitization by inhibition of cyclin-dependent kinase CDK9. It will discover whether clinically targetable CDKs are also epigenetic regulators and conduct pre-clinical and clinical studies of combined epigenetic therapy and immunotherapy using CDK inhibitors, DNA methyltransferase (DNMT) inhibitors and immune checkpoint inhibitors. The Core will analyze (i) gene expression and chromatin accessibility in tumor and immune cells in preclinical models of tumors treated with CDK9 inhibitors, (ii) genome-wide effects of CDK4, 6 and 7 inhibition on DNA methylation and gene expression, and (iii) support preclinical studies and a clinical trial combining CDK9, DNMT and immune checkpoints inhibitors by the analysis of collected samples for transcriptomic and epigenetic parameters (gene expression and expression of endogenous retroviruses and repetitive elements by RNA-seq, DNA methylation by RRBS) and immune cell parameters (gene expression and markers of exhaustion in sorted T cells). The Core will also perform whole exome sequencing (WES) to determine whether baseline DNA mutation and DNA methylation profiles predict response. Project 2 is focused on epigenetic synergy between inhibitors of DNMT and Polycomb repressive complex subunits EZH1/2 for therapy in solid tumors. The Core will analyze and integrate DNA methylation, ChIP-seq, RNA-seq and WES data to assess the combinatory effects of DNMT and EZH1/2 inhibitors and perform single-cell RNA-seq analysis of the tumor tissue to delineate tumor-associated immune populations. Project 3 combines induction of inflammasome signaling by hypomethylating agents with inhibitors of polyADP-ribosylation to induce death of cancer cells. The Core will assess genome-wide and LINE-1 repeat methylation. RNA-seq data will be analyzed for expression of ERVs and other repetitive elements in tumors and sorted immune cells.

摘要-基因组学、表观基因组学和生物信息学核心 基因组学、表观基因组学和生物信息学核心将提供人员、设备和专业知识 支持表观遗传疗法孢子的所有项目。核心将成为设计和执行的资源 基因组和表观基因组实验、数据获取、质量控制、生物信息学分析、数据 管理、共享和分发。它将与所有孢子项目和 病理学/生物质学核心。项目1研究通过抑制细胞周期蛋白依赖性激酶实现免疫增敏 CDK9。它将发现临床靶向的CDK是否也是表观遗传调节因子，并进行临床前研究 使用CDK抑制剂DNA进行表观遗传治疗和免疫联合治疗的临床研究 甲基转移酶(DNMT)抑制剂和免疫检查点抑制剂。核心将分析(I)基因 抗肿瘤药物治疗前肿瘤模型中肿瘤和免疫细胞中染色质的表达及染色质可及性 CDK9抑制剂，(II)抑制CDK4、6和7对DNA甲基化和基因表达的全基因组影响 表达，以及(Iii)支持临床前研究和结合CDK9、DNMT和免疫的临床试验 通过对收集的样本分析转录和表观遗传参数(基因 用RNA-seq、DNA甲基化方法表达和表达内源性逆转录病毒及重复元件 RRBS)和免疫细胞参数(分选T细胞中的基因表达和耗竭标记)。这个 CORE还将执行整个外显子组测序(WES)，以确定基线DNA突变和DNA 甲基化特征可以预测反应。项目2的重点是DNMT抑制剂之间的表观遗传协同作用。 和多梳抑制复合亚单位EZH1/2用于实体瘤的治疗。核心将分析和 结合DNA甲基化、CHIP-SEQ、RNA-SEQ和WES数据，评估DNMT和WES的联合作用 EZH1/2抑制剂，并对肿瘤组织进行单细胞RNA-SEQ分析以描绘与肿瘤相关的 免疫种群。项目3结合了去甲基化药物对炎症体信号的诱导 聚腺苷二磷酸核糖基化抑制剂可诱导癌细胞死亡。核心将评估全基因组和 Line-1重复甲基化。RNA-seq数据将分析ERV和其他重复序列的表达 肿瘤中的元素和已分类的免疫细胞。