Integrative Analysis of DNA Replication Timing in Cancer

癌症中 DNA 复制时间的综合分析

基本信息

批准号：
10523135
负责人：
Michael B Heskett
金额：
$ 8.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523135
关键词：
3-Dimensional Affect Alleles Back Behavior Bioinformatics Biological Assay Biological Models Biology Biometry Cancer Diagnostics Cancer Model Cell Line Cell model Cells Chromatin Chromatin Structure Chromosomal Loss Chromosomal Rearrangement Chromosomal Stability Chromosome 15 Chromosome 6 Chromosome Condensation Chromosome Deletion Chromosome Structures Chromosome abnormality Chromosomes Clone Cells Clustered Regularly Interspaced Short Palindromic Repeats Code Communities DNA Replication Timing DNA analysis DNA biosynthesis DNA replication fork Data Set Development Elements Event Family Fluorescent in Situ Hybridization Future Gene Expression Genes Genetic Nondisjunction Genetic Transcription Genome Genome Stability Genomic Instability Genomics Haplotypes Health Human Human Characteristics Human Chromosomes Human Cloning In Vitro Institutes Knowledge Lead Learning Link Maintenance Malignant Neoplasms Measures Medical Methods Mitotic Mitotic Chromosome Modeling Molecular Names Normal Cell Nucleotides Operative Surgical Procedures Patient-Focused Outcomes Phase Phenotype Physical condensation Population Postdoctoral Fellow Prognosis Progress Reports Proteins Public Speaking RNA Regulator Genes Research Role Route Sampling Single Nucleotide Polymorphism Testing The Cancer Genome Atlas Tissues Training Transcript Translating Untranslated RNA Work articular cartilage autosome cancer cell cancer genome cancer risk cancer type chromosome conformation capture chromosome missegregation clinically significant genome wide association study genome-wide insight interest lymphoblastoid cell line member novel diagnostics novel therapeutic intervention novel therapeutics pre-doctoral progenitor programs risk variant skill acquisition stem cells targeted cancer therapy therapy development tool tumor tumor progression virtual

项目摘要

Project Summary/Abstract: Genome instability is the most significant feature associated with poor prognosis in many cancers. But despite being a near-universal characteristic of human cancer, our knowledge of how genome instability initiates and contributes to tumor development is lacking. Because of its wide presence and close association with aggressive tumors, insight into the possible mechanisms and consequences of genome instability is crucial in the search for new and targeted cancer therapies and diagnostics. Here a new model is proposed, backed by significant preliminary findings, for the maintenance of genomic stability by cis-acting long non-coding RNA (lncRNA) elements that regulate multiple aspects of large-scale chromosome function. The main hypothesis of this project is that the recently discovered, cis-acting ASAR lncRNAs (ASynchronously Replicating Autosomal RNA), are expressed by normal cells on all autosomes to regulate fundamental chromosome behavior such as DNA replication timing, monoallelic gene expression, 3- dimensional chromosome localization, and mitotic chromosome condensation, but are frequently disrupted in cancer leading to genomic instability. Expression of the first two members of the ASAR family (ASAR6, ASAR15) is required for stability on chromosome 6 and 15 respectively, and disruption of either lncRNA leads to aberrant chromosomes through increased stalling of replication forks and mis-segregation of chromosomes. The long-term objective of this research is to identify all ASARs on human autosomes, validate their functional role in genome stability, and use ASARs as a tool to understand and ultimately identify and treat cancers with genomic instability. In Aim 1 a genome wide search for expression of putative ASARs will be performed utilizing a single-cell derived, haplotype-resolved human primary cell model system, followed by assessment of the functional qualities of potential ASARS with nucleotide sequencing assays that measure DNA replication timing, allele specific RNA expression, and 3D chromosome localization. To probe the potential effects of ASARs on human health, a search for significant disruption of ASARs in a dataset of ~10,000 human tumor samples will be performed. The research will be conducted as part of a comprehensive training plan involving advanced skill development in bioinformatics and biostatistics, professional development such as public speaking and networking, and will take place within an extensive intellectual community composed of cancer biologists at the Knight Cancer Institute, molecular and medical geneticists, and computational biologists at OHSU. The post-doctoral research direction will translate the knowledge of chromosome biology and skillsets in genomics developed during the pre-doctoral period to study the mechanisms of action of non protein-coding germline risk loci in human cancer. The successful results of the proposed research will reveal basic functions of chromosomes and provide new insight towards understanding genomic instability, a common abnormality in cancer.

项目摘要/摘要：基因组不稳定是与不良预后相关的最显着特征在许多癌症中。但是，尽管这是人类癌症的一个近乎普遍的特征，但我们对如何缺乏基因组不稳定性启动和促进肿瘤发展的机制。由于其广泛存在和与侵袭性肿瘤密切相关，深入了解基因组的可能机制和后果不稳定性对于寻找新的靶向癌症治疗和诊断至关重要。这里提出了一个新模型，以重要的初步发现为支持，用于维持基因组通过顺式作用的长非编码 RNA (lncRNA) 元件调节大规模的多个方面的稳定性染色体功能。该项目的主要假设是最近发现的顺式作用 ASAR lncRNA（异步复制常染色体RNA）由所有常染色体上的正常细胞表达调节基本染色体行为，例如 DNA 复制计时、单等位基因表达、3- 维度染色体定位和有丝分裂染色体浓缩，但经常被破坏癌症导致基因组不稳定。 ASAR家族前两个成员的表达（ASAR6， ASAR15) 分别是 6 号和 15 号染色体稳定性所必需的，并且任一 lncRNA 引线的破坏通过增加复制叉的停滞和染色体的错误分离来导致异常染色体。本研究的长期目标是识别人类常染色体上的所有 ASAR，验证其功能在基因组稳定性中的作用，并使用 ASAR 作为了解并最终识别和治疗癌症的工具基因组不稳定。在目标 1 中，将对假定的 ASAR 表达进行全基因组搜索利用单细胞衍生的、单倍型解析的人类原代细胞模型系统，然后评估通过测量 DNA 复制的核苷酸测序测定来确定潜在 ASARS 的功能质量时间、等位基因特异性 RNA 表达和 3D 染色体定位。探讨潜在影响 ASAR 对人类健康的影响，在约 10,000 个人类肿瘤的数据集中寻找 ASAR 的显着破坏将进行样品。该研究将作为涉及高级技能发展的综合培训计划的一部分进行生物信息学和生物统计学、公共演讲和网络等专业发展，并将是在由 Knight Cancer 的癌症生物学家组成的广泛知识界内进行的 OHSU 的研究所、分子和医学遗传学家以及计算生物学家。博士后研究方向将转化染色体生物学知识和基因组学技能博士前期间研究人类非蛋白编码种系风险位点的作用机制癌症。该研究的成功结果将揭示染色体的基本功能和为理解基因组不稳定性（癌症中常见的异常）提供了新的见解。