Novel markers of exposure and pathways of response to Chromium

铬暴露和反应途径的新标记

基本信息

批准号：
10666906
负责人：
Bernardo Lemos
金额：
$ 20.75万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666906
关键词：
Address Affect Animal Model Architecture Biogenesis Biology Carcinogens Cell Cycle Progression Cell Nucleolus Cell Nucleus Cell model Cell physiology Cells Cellular biology Chemicals China Chromatin Chromium Chromosome Segregation Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Damage DNA Repair DNA amplification DNA copy number Data Dose Drosophila genus Elements Epigenetic Process Epithelial Cells Exposure to Gene Dosage Gene Expression Gene Silencing Genes Genetic Genetic Determinism Genetic Transcription Genome Genome Components Genomics Germany Health Heterochromatin Human Induced Mutation Information Resources Injury Investigation Knock-out Light Lung Malignant Neoplasms Mammalian Cell Maps Mediating Medical Metal exposure Metals Mission Mus NCI Center for Cancer Research National Institute of Environmental Health Sciences Nuclear Occupational Oncogenes Organelles Pathway interactions Play Population Process Public Health RNA Reactive Oxygen Species Recovery Research Resolution Rest Ribosomal DNA Ribosomal RNA Ribosomes Role Seminal Site Stress Superoxide Dismutase TP53 gene Techniques Technology Testing Time Tissues Toxic Environmental Substances Toxic effect Toxicology United States National Institutes of Health Variant Work carcinogenesis chromium hexavalent ion directed attention drinking water expectation exposure pathway functional genomics gain of function mutation gene interaction genetic analysis genome-wide human disease individual response loss of function novel novel marker nucleolar organizing region recruit response skills

项目摘要

Abstract Cr(VI) is a human carcinogen of significant public health concern, and a substantial exposure in a number of occupational settings. Cr(VI) induces mutations, changes in gene copy number, and exposure has been associated with humans cancers in exposed populations and animal models. Our novel preliminary data demonstrate that Cr(VI) exposure causes amplification in ribosomal DNA (rDNA) copy number and changes in the nucleolus (the crudely understood nuclear organelle that is the site of ribosomal RNA (rRNA) transcription, and integration of myriad cellular functions). A crucial element of nucleolar function is rDNA copy number (rDNA CN). rDNA CN modulates (i) epigenetic states across the genome, (ii) DNA damage responses, (iii) cell cycle progression, (iv) chromosome segregation, and (v) global genetic stability. Furthermore, disruption of rDNA arrays, ribosome biogenesis, and the nucleolus are central to carcinogenesis. Our central medical hypothesis is that Cr-induced changes in rDNA CN are responsible for Cr-induced carcinogenesis. Our central basic hypothesis is that rDNA arrays are not fixed, but rather a genetically dynamic component of the nuclear genome with copy number that is modulated by Cr exposure. Our proposal examines rDNA changes upon Cr(VI) exposure to reveal a novel pathway of Cr toxicity with medical and basic relevance. Key elements are a careful investigation of the toxicology of Cr-induced-rDNA-amplification (Cr-i-rDNA-a), hypotheses-driven functional genomic analysis the rDNA and the nucleolus upon Cr(VI) exposure, and extensive genetic analyses of Cr-i-rDNA-a using a powerful model organism. Our first aim will investigate the toxicology of Chromium- induced-rDNA-amplification (Cr-i-rDNA-a) in a human lung epithelial cell model. We will determine dose- responses of Cr-i-rDNA-a, map amplification boundaries in Cr-i-rDNA-a, examine temporal profiles and recovery from Cr(VI) exposure, and examine whether Chromium-induced CN changes are responsible for Cr- induced carcinogenesis. Our second aim investigates the functional genomics of Cr-induced nucleolar stress and Cr induced transformation in a human lung epithelial cell model. Examining genome-wide responses to Cr exposure is critical to understand how Cr induces rDNA amplification, nuclelar stress, and carcinogenesis. Our third aim addresses the genetic determinants of Chromium-rDNA interactions. We will examine Cr-i-rDNA-a in specific cells, quantify the extent of copy number change, isolate the affected tissues, and use high-throughput techniques to characterize the changes. Our efforts will shed light on Cr-rDNA interactions, with research that is directly relevant to the human health mission of the NIH. The manifold effects of rDNA CN indicate that perturbing this central regulator with Cr will have profound consequences to cellular function. We anticipate that determinants of complex human diseases with strong environmental components such as cancer will ultimately be traced to environmentally triggered variation in rDNA segments of the genome.

抽象的 CR（vi）是一种重要的公共卫生关注的人类致癌物，许多职业环境。 CR（VI）诱导突变，基因拷贝数的变化以及暴露是与裸露人群和动物模型中的人类癌症有关。我们的新型初步数据证明CR（VI）暴露会导致核糖体DNA（rDNA）拷贝数和变化核仁（粗略理解的核细胞器）是核糖体RNA（rRNA）转录的位点，和无数细胞函数的整合）。核仁函数的关键要素是rDNA拷贝数（rDNA CN）。 rDNA CN调节基因组跨基因组的表观遗传态，（ii）DNA损伤反应，（iii）细胞循环进程，（IV）染色体分离和（v）全球遗传稳定性。此外，中断 rDNA阵列，核糖体生物发生和核仁是癌变的核心。我们的中央医疗假设是CR诱导的rDNA CN的变化负责CR诱导的致癌作用。我们的中心基本假设是rDNA阵列不是固定的，而是核的遗传动态成分具有CR暴露调节的拷贝数的基因组。我们的建议检查了rDNA的变化 CR（VI）暴露，以揭示具有医学和基本相关性的CR毒性的新途径。关键元素是仔细研究CR诱导RDNA扩增的毒理学（CR-I-RDNA-A），假设驱动的功能基因组分析Cr（VI）暴露后的rDNA和核仁，以及广泛的遗传分析使用强大的模型生物的Cr-i-rDNA-a。我们的第一个目标将研究铬的毒理学在人肺上皮细胞模型中诱导RDNA扩增（CR-I-RDNA-A）。我们将确定剂量 - CR-I-RDNA-A的响应，CR-I-RDNA-A中的MAP扩增边界，检查时间曲线和从CR（VI）暴露中恢复，并检查铬诱导的CN变化是否导致CR- 诱导的致癌作用。我们的第二个目标研究了CR诱导的核仁应力的功能基因组学 CR诱导的人类肺上皮细胞模型中的转化。检查全基因组对CR的反应暴露对于了解CR如何诱导rDNA扩增，核素应激和癌变至关重要。我们的第三目的针对铬-RDNA相互作用的遗传决定因素。我们将检查Cr-i-rdna-a 特定的细胞，量化拷贝数变化的程度，隔离受影响的组织并使用高通量表征更改的技术。我们的努力将阐明CR-RDNA互动，并通过研究与NIH的人类健康任务直接相关。 rDNA CN的歧管效应表明用CR扰动该中央调节剂将对细胞功能产生深远的影响。我们期待具有强大环境成分（例如癌症）的复杂人类疾病的决定因素将最终可追溯到基因组rDNA段的环境触发的变化。