Molecular Tumorigenesis of Bladder Cancer

膀胱癌的分子肿瘤发生

基本信息

批准号：
10229411
负责人：
XUE-RU WU
金额：
$ 136.59万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-12 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229411
关键词：
Affect Apoptotic Authorship Awareness BIRC4 gene Basic Science Biological Biological Assay Biological Markers Biology Bladder Cells Clinical Research Cultured Cells DNA Damage DNA Repair Data Development Diagnosis Differentiation and Growth Disease Distant Electronic cigarette Ensure Funding Genetic Genetic Engineering Genetic study Genetically Engineered Mouse Heterogeneity High Prevalence Human Incidence Investigation Joints Knowledge Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Medical Medical Care Costs Modeling Molecular Moon Mus Muscle Mutation Neoplasm Metastasis Nicotine Nitrosamines Outcome Paper Papillary Pathway interactions Phenotype Plant Roots Play Productivity Proteins Publishing Reagent Recording of previous events Research Personnel Research Project Grants Role Seminal Services Signal Pathway Signal Transduction Survival Rate Testing Tobacco smoke Translational Research United States Urothelial Cell Urothelial Hyperplasia Urothelium Variant Woman Work base bladder cancer prevention cancer cell cancer heterogeneity carcinogenicity chemical carcinogenesis cigarette smoke-induced combinatorial cost cost effectiveness e-cigarette smoke exome exposure to cigarette smoke immune checkpoint blockade in vivo innovation interdisciplinary approach lifetime risk men molecular subtypes mouse genetics muscle invasive bladder cancer novel novel marker novel therapeutic intervention novel therapeutics operation prevent programs stem cells theranostics therapeutically effective transcriptome tumorigenesis vapor whole genome

项目摘要

Overall: Project Summary Of the most prevalent cancers in the United States over the last three decades, bladder cancer (BC) has consistently ranked the fifth in annual incidence and the first in medical expenses on a per-case basis. Despite its high prevalence and staggering medical costs, BC is until recently among the least studied cancers with limited efforts in basic, translational and clinical research. Consequently, few assays and biomarkers exist to reliably diagnose BC and predict its progression and few new therapeutic approaches are available to effectively manage BC. Compounding this is the fact that BC is highly heterogeneous comprised of major phenotypic variants and molecular subtypes, as evidenced by previous genetic studies and recent whole- genome/-exome/transcriptome analyses. Over the last five years, the investigators of our PO1 Team have worked together in a highly synergistic and collaborative manner in tackling the biological bases of BC heterogeneity and made significant strides in: discerning the combinatorial genetic drivers of major BC variants; establishing DNA damage and repair as distinguishing features of different types of BC; establishing XIAP as a critical driver of BC invasion; and identifying urothelial subpopulations as potential progenitor cells of BC variants. This renewal application builds on this forward momentum and focuses on a much deeper and expanded scientific theme – the genetic, carcinogenomic, molecular and cellular underpinnings of BC heterogeneity, by asking several important new questions. What dictates the origin(s) of major BC variants: divergent genetic drivers versus divergent progenitor cells (Project 1; P1)? Do the nitrosamines converted from nicotine in E-cigarette vapor within host cells cause muscle-invasive BC and how do they affect urothelial DNA damage and repair (P2)? And is there a master switch that drives the formation of basal-subtype muscle- invasive BC (P3)? Results from this highly coordinated, collaborative team effort should contribute to the major leap forward in our understanding of the biological bases of BC heterogeneity, leading to the development of novel biomarkers and therapeutics for this highly prevalent but extremely under-studied disease.

总体：项目摘要在过去三十年中，美国最普遍的癌症中，膀胱癌（BC）有一贯在年度事件中排名第五，并且是每盘人的医疗费用。尽管卑诗省的高龄和惊人的医疗费用，直到最近才是研究癌症的最少的癌症在基本，翻译和临床研究方面的努力有限。因此，很少有测定和生物标志物存在可靠地诊断不列颠哥伦比亚省并预测其进展，很少有新的治疗方法可用于有效地管理BC。复杂的事实是，卑诗省高度异质地积累了主要的主要表型变异和分子亚型，以前的遗传研究和最近的整体证明了基因组/ - 异常/转录组分析。在过去的五年中，我们的PO1团队的调查人员有以高度协同和协作的方式共同努力，以应对卑诗省的生物基础异质性并取得了重大进步：辨别主要BC的组合遗传驱动因素变体；建立DNA损伤和修复为不同类型BC的特征；建立 XIAP是卑诗省入侵的关键驱动力；并确定尿路上皮亚群是潜在的祖细胞 BC变体。此更新应用程序以这种向前的势头为基础，专注于更深层次的扩展的科学主题 - 遗传，致癌，分子和细胞基础卑诗省的基础异质性，提出几个重要的新问题。是什么决定了卑诗省主要变体的起源：遗传驱动因素与发散的祖细胞（项目1; P1）？从转换的亚硝胺转换宿主细胞内电子烟蒸气中的尼古丁引起肌肉侵入性BC，它们如何影响尿路上皮DNA 损坏和维修（P2）？并且是否有一个主开关，可以驱动基本的肌肉肌肉的形成侵入性BC（P3）？这项高度协调的协作团队努力的结果应为专业做出贡献在我们对BC异质性生物基础的理解中飞跃，导致了新型生物标志物和这种高度流行但极为研究的疾病的疗法。