Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

膀胱癌中的染色质修饰基因突变和增强子功能障碍

• 批准号: 10579885
• 负责人: Byron H Lee
• 金额: $ 24.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579885
• 关键词: ATAC-seq; Acetylation; Affect; Anchorage-Independent Growth; Behavior; Benign; Bioinformatics; Biological; Biological Assay; Biology; CREBBP gene; Cancer Biology; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Loop; Chromatin Remodeling Factor; Cisplatin; Climacteric; Clinical; Combined Modality Therapy; Complex; Comprehensive Cancer Center; DNA; DNA-Binding Proteins; Data; Dependence; Development; Disease; Dominant-Negative Mutation; EP300 gene; Enhancers; FDA approved; Freezing; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genitourinary system; Goals; Growth; High-Throughput Nucleotide Sequencing; Histone H3; Histones; Human; Immune checkpoint inhibitor; In Vitro; Injections; Institutional Review Boards; Intercistronic Region; Invaded; Knock-out; Lysine; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mentors; Methyltransferase; Molecular; Mus; Mutate; Mutation; National Human Genome Research Institute; Neoadjuvant Therapy; Neoplasms; Operative Surgical Procedures; Organoids; Patient Care; Patients; Pattern; Phenotype; Physicians; Play; Proliferating; Proteins; Protocols documentation; Radical Cystectomy; Regulatory Element; Research; Research Personnel; Role; Sampling; Scientist; Shapes; Small Interfering RNA; Specimen; Tamoxifen; Testing; The Cancer Genome Atlas; Training; Training Support; Translational Research; Transposase; United States; Universities; Urinary tract; Urothelial Cell; Urothelium; biobank; cancer cell; cancer initiation; cancer therapy; cell motility; chemotherapy; epigenomics; exome sequencing; gain of function; genetic corepressor; histone acetyltransferase; improved; in vivo; knock-down; loss of function; member; mortality; mouse model; muscle invasive bladder cancer; mutational status; non-muscle invasive bladder cancer; novel therapeutics; professor; programs; promoter; protein complex; reconstruction; response; small molecule inhibitor; standard of care; synthetic lethal interaction; targeted treatment; transcription factor; transcriptome sequencing; treatment response; tumor progression

Project Summary and Abstract The overall goal of this proposal is to support the training of Dr. Byron Lee to become an independent investigator conducting translational research in bladder cancer epigenomics. Dr. Lee will be mentored by Dr. Nima Sharifi and Dr. Peter Scacheri. Dr. Nima Sharifi is the leader of the Genitourinary Malignancies Program at the Case Comprehensive Cancer Center and has mentored numerous young physician-scientists. Dr. Peter Scacheri is Professor of Genetics at Case Western Reserve University and an expert in cancer epigenomics. The training plan incorporates the following goals: (1) enhance understanding of chromatin biology, (2) gain expertise in bioinformatics analysis of complex biological data, and (3) develop proficiency in the use of patient-derived samples for translational research. Bladder cancer is the fifth most common non-cutaneous malignancy in the United States, yet few new treatment options exist. The Cancer Genome Atlas (TCGA), a large-scale effort supported by NCI and NHGRI to determine the molecular basis of cancer, performed comprehensive molecular characterization of over 400 muscle invasive bladder cancers and showed that chromatin modifier gene alterations occur in 75% of cases. Most of these alterations are predicted to result in loss of function; however, their effects on bladder cancer initiation, progression, and response to therapy are largely unknown. These genes alter the configuration of the DNA-histone interface, which affects the ability of DNA-binding proteins to access their target sequences. The central hypothesis that will be tested is that chromatin modifier gene mutation leads to gene expression changes that support bladder cancer initiation and progression through enhancer disruption. To accomplish this goal, we propose the following Specific Aims: (1) Test the hypothesis that KDM6A inactivation alters the chromatin state of urothelial cells and engenders a transcriptional program that results in neoplastic growth, and (2) Test the hypothesis that enhancer dysfunction and aberrant transcriptional circuits characterize human bladder cancer and dependence on these circuits for growth result in vulnerability to existing targeted therapies. Successful completion of the proposed research will advance our understanding of how chromatin modifier gene mutations, one of the most frequent somatic alterations in bladder cancer, affect disease initiation and progression. Moreover, we expect to identify molecular vulnerabilities arising from enhancer disruption and changes in transcription factor circuits. Targeting these vulnerabilities can lead to the development of novel therapies for bladder cancer.

项目概要和摘要 本提案的总体目标是支持培训Byron Lee博士，使其成为一名独立调查员 进行膀胱癌表观基因组学的转化研究。李博士将由Nima Sharifi博士指导 和彼得·斯卡切里博士Nima Sharifi博士是病例中心泌尿生殖系统肿瘤项目的负责人。 综合癌症中心，并指导了许多年轻的医学科学家。彼得·斯卡切里博士是 凯斯西储大学遗传学教授，癌症表观基因组学专家。培训 该计划包括以下目标：（1）提高对染色质生物学的理解，（2）获得以下方面的专业知识： 复杂生物数据的生物信息学分析，以及（3）熟练使用患者来源的 翻译研究的样本。膀胱癌是世界上第五大最常见的非皮肤恶性肿瘤。 美国，但很少有新的治疗选择。癌症基因组图谱（TCGA），一个大规模的努力， 在NCI和NHGRI的支持下，确定癌症的分子基础，进行了全面的分子生物学研究。 对400多例肌肉浸润性膀胱癌进行了表征，并显示染色质修饰基因 在75%的病例中发生了改变。这些改变中的大多数被预测会导致功能丧失;然而， 它们对膀胱癌的发生、发展和对治疗的反应的影响在很大程度上是未知的。这些基因 改变DNA-组蛋白界面的构型，从而影响DNA结合蛋白进入 它们的目标序列。将要检验的中心假设是染色质修饰基因突变导致 通过增强子破坏支持膀胱癌发生和发展的基因表达变化。 为了实现这一目标，我们提出了以下具体目标：（1）检验KDM 6A失活的假设， 改变尿路上皮细胞的染色质状态，并产生一个转录程序，导致肿瘤 生长，和（2）测试增强子功能障碍和异常转录回路表征的假设 人类膀胱癌和对这些回路生长依赖导致对现有靶向 治疗成功完成拟议的研究将推进我们对染色质如何 修饰基因突变是膀胱癌中最常见的体细胞改变之一， 和进步。此外，我们希望确定增强子破坏引起的分子脆弱性， 转录因子回路的变化。针对这些漏洞可以导致开发新的 膀胱癌的治疗