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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要和摘要该提案的总体目标是支持拜伦·李博士的培训，成为一名独立研究者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（Peter Scacheri）博士。 Nima Sharifi博士是该案的泌尿生殖器恶性肿瘤计划的负责人综合癌症中心，并指导了许多年轻的医师科学家。彼得·斯卡切里（Peter Scacheri）博士是 Case Western Reserve University的遗传学教授和癌症表观基因组学专家。培训计划包含以下目标：（1）增强对染色质生物学的了解，（2）获得专业知识复杂生物学数据的生物信息学分析，以及（3）在使用患者衍生的使用方面熟练转化研究的样本。膀胱癌是在美国，但很少有新的治疗选择。癌症基因组地图集（TCGA），这是一项大规模的努力由NCI和NHGRI支持确定癌症的分子基础，进行了全面的分子超过400个肌肉浸润性膀胱癌的表征，表明染色质修饰剂基因 75％的病例发生了改变。这些改变大多数被预测会导致功能丧失。然而，它们对膀胱癌启动，进展和对治疗的反应的影响在很大程度上是未知的。这些基因更改DNA-固定界面的配置，这会影响DNA结合蛋白访问的能力他们的目标序列。将要测试的中心假设是染色质修饰剂基因突变导致基因表达会改变，从而通过增强子破坏来支持膀胱癌的启动和进展。为了实现这一目标，我们提出以下特定目的：（1）检验KDM6A失活的假设改变尿路上皮细胞的染色质状态并产生导致肿瘤的转录程序生长和（2）测试以下假设：增强子功能障碍和异常转录电路的特征是人类膀胱癌和对这些电路的依赖性增长导致对现有目标的脆弱性疗法。成功完成拟议的研究将提高我们对染色质的理解修饰剂基因突变是膀胱癌最常见的躯体改变之一，会影响疾病起步和进展。此外，我们希望确定因增强子破坏和转录因子电路的变化。针对这些漏洞可以导致新颖的发展膀胱癌的疗法。