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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：
10341147
负责人：
Byron H Lee
金额：
$ 24.32万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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 2023-01-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341147
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 Lead Lysine Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Mentors Metastatic to Methyltransferase Molecular Mus Mutate Mutation National Human Genome Research Institute Neoadjuvant Therapy Neoplasms Operative Surgical Procedures Organoids Patient Care Patients Pattern Phenotype Physicians Play 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 base 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 overtreatment professor programs promoter protein complex reconstruction response small molecule inhibitor standard of care 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.

项目摘要及摘要