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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.

摘要