Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
基本信息
- 批准号:10601677
- 负责人:
- 金额:$ 35.86万
- 依托单位:
- 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:2022-08-23 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAnimalsApoptosisAttentionBiological MarkersCancer EtiologyCarcinogensCell LineCellsCessation of lifeChromosomal InstabilityClone CellsCollectionColon CarcinomaComplexDNA RepairDNA Repair PathwayDNA SequenceDataDiseaseEnvironmentEnvironmental HealthEpithelialEpithelial CellsEventExposure toFibroblastsFundingGenesGenomeGenomicsGrantHazardous SubstancesHealthHeritabilityHumanHuman CloningIndividualKnowledgeLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMeasuresMetal CarcinogenesisMetal exposureMetalsMicrosatellite InstabilityMicrosatellite RepeatsMinorityMismatch RepairMutagensNational Institute of Environmental Health SciencesNeoplastic Cell TransformationOutcomeParentsParticulatePathway interactionsPersonsPopulationPublic HealthRisk AssessmentRisk ManagementRoleRouteStructureStructure of parenchyma of lungTissuesTobaccoTobacco useTranslatingUnited StatesWorkWorkplacecancer stem cellcarcinogenesiscarcinogenicitycell typechromium hexavalent ionenvironment related cancergene repairgenome sequencinghuman subjectimprovedin vivoinduced pluripotent stem cellinnovationinsightinterestmalignant breast neoplasmmixed cell cultureneoplasticnext generationnovelnovel strategiesparent grantpreventprogramsrepairedsocial stigmastem cell modeltargeted biomarkertherapeutic targettobacco usertooltumor progressionwhole genome
项目摘要
PROJECT SUMMARY OF THE FUNDED PARENT GRANT
Lung cancer is the leading cause of cancer death with little improvement in survivability over many decades.
Understanding and support for lung cancer have suffered from the stigma that the disease is merely a
consequence of tobacco use, when in fact other agents are a major factor in the disease. Many people with lung
cancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However, while
lung cancer kills more people than colon, breast and prostate cancer combined, it receives less federal funding
than each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All established
lung carcinogens cause CIN, yet the mechanisms for how they do have received little attention. Metal exposure
is a worldwide health concern. Metals cause lung cancer, and carcinogenic metals are a component in tobacco.
Metals are poor mutagens but potently induce CIN, yet, how metals cause lung cancer and CIN is poorly
understood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induce
CIN in lung cancer. We use hexavalent chromium [Cr(VI)], a human lung carcinogen of major public health
concern, as our primary metal of interest, although we will compare Cr(VI) outcomes with other metal lung
carcinogens. We will study how Cr(VI) induces structural and numerical CIN, considering human lung fibroblast,
epithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types to
more complex, three-dimensional, mixed cell culture studies. We enhance and deepen our understanding of
these mechanisms with a One Environmental Health approach, which leverages the ability of wildlife to resist
Cr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover, we maximize the
impact of these findings by translating our outcomes into animals and into a powerful and unique collection of
human subjects and populations ranging from workers with primarily Cr(VI) exposure, to workers with a mixed
metal exposure including Cr. This combined approach of humans, animals and cell lines with One Environmental
Health tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particular,
we will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable at
the cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus, our
proposed R35 program will revolutionize our understanding of Cr(VI), CIN, metal carcinogenesis, and lung
cancer while also providing important insights for other cancers that involve CIN. Outcomes will include major
scientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;
2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells that
have transformed and 4) how to prevent neoplastic change from occurring, leading to improved risk assessment,
treatments, and health outcomes for people exposed to metals.
基金资助的奖学金项目摘要
肺癌是癌症死亡的主要原因,几十年来生存率几乎没有改善。
对肺癌的理解和支持一直受到这种疾病仅仅是一种
事实上,其他因素也是导致这种疾病的主要因素。很多人肺
癌症患者从未使用过烟草,只有少数烟草使用者实际上会患肺癌。虽然
肺癌比结肠癌、乳腺癌和前列腺癌的死亡人数总和还要多,但它得到的联邦资助却更少
比单独的这些癌症都要多染色体不稳定性(CIN)是肺癌的标志。所有既定
肺致癌物导致CIN,但其机制却很少受到关注。金属暴露
是一个全球性的健康问题。金属会导致肺癌,致癌金属是烟草中的一种成分。
金属是不良的诱变剂,但可诱发CIN,然而,金属如何导致肺癌和CIN是不良的
明白我们的R35计划重点是了解金属致癌物如何诱导
肺癌的CIN。我们使用六价铬[Cr(VI)],一种主要的公共卫生人类肺癌致癌物
尽管我们将比较Cr(VI)与其他金属肺的结局,
致癌物质。我们将研究Cr(VI)如何诱导结构和数值CIN,考虑人肺成纤维细胞,
上皮和诱导多能干细胞模型。我们将从单个细胞类型的研究进展到
更复杂的三维混合细胞培养研究。我们加强和加深对以下方面的了解:
这些机制与一个环境健康的方法,利用野生动物的能力,以抵抗
Cr(VI)诱导的CIN,并提供新的见解,其致癌机制。此外,我们最大限度地
这些发现的影响,通过将我们的结果转化为动物,并转化为一个强大的和独特的收集,
人类受试者和人群,从主要接触Cr(VI)的工人到混合接触Cr(VI)的工人,
金属暴露,包括Cr。这种结合人类、动物和细胞系的方法,
健康工具将使我们前所未有地深入了解金属如何诱导结构和数值CIN。特别是,
我们将定义:1)金属诱导的CIN的关键机制; 2)这些机制如何持续存在,并在
细胞水平导致肿瘤疾病; 3)它们如何转化为动物和人类。所以我们
拟议的R35计划将彻底改变我们对Cr(VI),CIN,金属致癌作用和肺的理解
同时也为涉及CIN的其他癌症提供了重要的见解。成果将包括:
在理解方面的科学突破:1)金属如何导致正常人类肺细胞成为肿瘤;
2)如何在肿瘤发生时检测到这种肿瘤转化; 3)如何更有效地靶向肺细胞,
4)如何预防肿瘤变化的发生,从而改善风险评估,
治疗和健康结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John Pierce Wise其他文献
Global assessment of oceanic lead pollution using sperm whales (<em>Physeter macrocephalus</em>) as an indicator species
- DOI:
10.1016/j.marpolbul.2013.12.007 - 发表时间:
2014-02-15 - 期刊:
- 影响因子:
- 作者:
Laura C. Savery;Sandra S. Wise;Carolyne Falank;James Wise;Christy Gianios;W. Douglas Thompson;Christopher Perkins;Tongzhang Zheng;Cairong Zhu;John Pierce Wise - 通讯作者:
John Pierce Wise
Does aluminum exposure of pregnant animals lead to accumulation in mothers or their offspring?
怀孕动物接触铝是否会导致母亲或其后代体内积累铝?
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
J. Borak;John Pierce Wise - 通讯作者:
John Pierce Wise
Particulate hexavalent chromium inhibits global transcription of genes in DNA repair pathways, particularly targeting homologous recombination repair, base excision repair, mismatch repair and microhomology-mediated end-joining
颗粒状六价铬抑制 DNA 修复途径中基因的整体转录,尤其靶向同源重组修复、碱基切除修复、错配修复和微同源介导的末端连接。
- DOI:
10.1016/j.jhazmat.2024.136892 - 发表时间:
2025-03-05 - 期刊:
- 影响因子:11.300
- 作者:
Idoia Meaza;Caitlin R. Cahill;Rachel M. Speer;J. Calvin Kouokam;John Pierce Wise - 通讯作者:
John Pierce Wise
Global assessment of arsenic pollution using sperm whales (<em>Physeter macrocephalus</em>) as an emerging aquatic model organism
- DOI:
10.1016/j.cbpc.2014.01.003 - 发表时间:
2014-06-01 - 期刊:
- 影响因子:
- 作者:
Laura C. Savery;James T.F. Wise;Sandra S. Wise;Carolyne Falank;Christy Gianios;W. Douglas Thompson;Christopher Perkins;Tongzhang Zheng;Cairong Zhu;John Pierce Wise - 通讯作者:
John Pierce Wise
Carcinogenic Mechanisms of Hexavalent Chromium: From DNA Breaks to Chromosome Instability and Neoplastic Transformation
- DOI:
10.1007/s40572-024-00460-9 - 发表时间:
2024-10-28 - 期刊:
- 影响因子:9.100
- 作者:
Idoia Meaza;Aggie R. Williams;Sandra S. Wise;Haiyan Lu;John Pierce Wise - 通讯作者:
John Pierce Wise
John Pierce Wise的其他文献
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{{ truncateString('John Pierce Wise', 18)}}的其他基金
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10655683 - 财政年份:2022
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10459886 - 财政年份:2022
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10883861 - 财政年份:2022
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10792258 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学
- 批准号:
10359325 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10456862 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10656428 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Cr(VI)-Induced DNA Damage Contributes to Brain Aging
Cr(VI) 诱导的 DNA 损伤导致大脑衰老
- 批准号:
10287080 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Chromosome Instability Drives Metal-Induced Lung Cancer
染色体不稳定性导致金属诱发肺癌
- 批准号:
10198235 - 财政年份:2021
- 资助金额:
$ 35.86万 - 项目类别:
Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
人肺上皮细胞和成纤维细胞中的颗粒 Cr(VI) 毒理学
- 批准号:
8074274 - 财政年份:2010
- 资助金额:
$ 35.86万 - 项目类别:
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