Repair of HCMV-Induced DNA Damage in Infected Cells
修复受感染细胞中 HCMV 诱导的 DNA 损伤
基本信息
- 批准号:8589573
- 负责人:
- 金额:$ 31.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-12-15 至 2016-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAreaAuditory systemBinding ProteinsBiological AssayBiological ModelsBlindnessBrainCaringCell Differentiation processCell physiologyCellsChildChromosome MappingChromosomesClinicalCongenital AbnormalityCytomegalovirusCytomegalovirus InfectionsDNADNA DamageDNA RepairDefectDevelopmentDiagnosisDown SyndromeDown-RegulationEnzymesExhibitsFibroblastsFluorescent in Situ HybridizationFundingGenesGoalsHumanIn VitroInfantInfectionInterphaseLinkLytic PhaseMental RetardationMessenger RNAMicrocephalyMolecularMonitorMyelin P0 ProteinNeonatalNeuraxisNeuronsParentsPlayPopulationProteinsResearchRoleSamplingSiteSpecimenStem cellsSyndromeTestingTimeTissuesTranslatingViral AntigensViral ProteinsVirionVirusWorkbrain tissuecongenital infectiondimereconomic costfetalhearing impairmentimprovedin vitro Modelinterestmigrationneonatenerve stem cellnidogen-1preventpublic health relevancerepairedresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Human Cytomegalovirus (HCMV) is a leading cause of birth defects. Ramifications of HCMV infection are primarily observed in the central nervous system (CNS) and include hearing loss, vision loss, microcephaly and mental retardation. Despite considerable effort, the underlying mechanisms causing these CNS defects remain unknown. Our previously funded studies of HCMV interaction with the host cell DNA and its DNA repair machinery have identified three areas of particular interest to pursue. First, HCMV is one of only two viruses known to inflict site-specific chromosomal damage to the host DNA. Fine mapping of the chromosome 1q breaksites has revealed two genes, nidogen 1 (NID1) and myelin protein zero (MPZ), linked to the development of hearing loss in infected infants. Second, studies on DNA repair in HCMV infected permissive fibroblasts found that, although DNA damage responses were activated during infection, they were not completed. We suspect that compromised repair of specific and nonspecific DNA damage may play a role in the development of HCMV-induced birth defects. Third, we have recently begun working with a promising new in vitro model, the Neural Progenitor Cell (NPCs), and its derivatives. These cells, derived from post mortem neonatal brain tissue, provide a unique opportunity to investigate HCMV infection in a model system directly relevant to the human fetal CNS. NPCs, their glial derivatives, and the large majority of their neuronal derivatives, are fully permissive and suffer a lytic infection. However, a subpopulation of differentiated neurons, although permissive, exhibit extended viral antigen expression and release of virions. The long term goal of our work is to translate the information gained from studying infection in vitro, into understanding the development of CNS defects in congenitally infected infants. We propose examining clinical specimens for confirmatory evidence of the results found in our in vitro experiments. We have procured sample archival brain and auditory system tissues from neonates that have succumbed to HCMV infection, which will feature prominently in our proposed experiments. We will advance our long term goal with the testing of four hypotheses: 1) that a viral protein (or proteins) induces the site-specific breaks on Chromosome 1q; 2) that the compromised repair of HCMV-induced breaks causes downregulation of breaksite-encoded genes; 3) that HCMV disrupts the cellular DNA repair machinery's ability to repair non-specific damage in neural cells; and 4) that HCMV infection within the CNS affects expression of specific genes involved in differentiation, migration and cell function in NPCs and long-term neurons. The experiments described in this proposal will provide a detailed understanding of the molecular mechanisms underlying the genesis of HCMV-induced birth defects and contribute to the development of strategies to interrupt these mechanisms and, hopefully, prevent their frequently devastating consequences.
描述(由申请人提供):人巨细胞病毒(HCMV)是导致出生缺陷的主要原因。HCMV感染的分支主要在中枢神经系统(CNS)中观察到,并且包括听力损失、视力损失、小头畸形和智力迟钝。尽管付出了相当大的努力,但导致这些CNS缺陷的潜在机制仍然未知。我们以前资助的HCMV与宿主细胞DNA及其DNA修复机制相互作用的研究已经确定了三个特别感兴趣的领域。首先,HCMV是已知对宿主DNA造成位点特异性染色体损伤的仅有的两种病毒之一。染色体1 q断裂位点的精细定位揭示了两个基因,巢蛋白1(NID 1)和髓鞘蛋白零(MPZ),与感染婴儿听力损失的发展有关。其次,对HCMV感染的容许成纤维细胞中的DNA修复的研究发现,尽管DNA损伤反应在感染期间被激活,但它们并没有完成。我们怀疑特异性和非特异性DNA损伤的修复受损可能在HCMV诱导的出生缺陷的发展中起作用。第三,我们最近开始研究一种有前途的新体外模型,神经祖细胞(NPC)及其衍生物。这些细胞,来自死后新生儿脑组织,提供了一个独特的机会,调查HCMV感染的模型系统直接相关的人胎儿中枢神经系统。NPC、它们的神经胶质衍生物和它们的大部分神经元衍生物是完全容许的,并且遭受溶解性感染。然而,分化的神经元的亚群,虽然允许,表现出延长的病毒抗原表达和释放的病毒粒子。我们工作的长期目标是将从体外研究感染中获得的信息转化为了解先天性感染婴儿CNS缺陷的发展。我们建议检查临床标本,以获得体外实验结果的确证性证据。我们已经从死于HCMV感染的新生儿中获得了存档的大脑和听觉系统组织样本,这将在我们提出的实验中发挥重要作用。我们将通过测试四个假设来推进我们的长期目标:1)病毒蛋白质(或蛋白质)诱导染色体1 q上的位点特异性断裂; 2)HCMV诱导的断裂的修复受损导致断裂位点编码基因的下调; 3)HCMV破坏细胞DNA修复机制修复神经细胞非特异性损伤的能力;和4)CNS内的HCMV感染影响参与NPC和长期神经元中的分化、迁移和细胞功能的特异性基因的表达。本提案中描述的实验将详细了解HCMV诱导的出生缺陷发生的分子机制,并有助于制定中断这些机制的策略,并有望防止其经常发生的破坏性后果。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bromodeoxyuridine-labeled viral particles as a tool for visualization of the immediate-early events of human cytomegalovirus infection.
溴脱氧尿苷标记的病毒颗粒作为人类巨细胞病毒感染早期事件可视化的工具。
- DOI:10.1128/jvi.78.14.7818-7822.2004
- 发表时间:2004
- 期刊:
- 影响因子:5.4
- 作者:Rosenke,Kyle;Fortunato,ElizabethA
- 通讯作者:Fortunato,ElizabethA
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ELIZABETH A FORTUNATO其他文献
ELIZABETH A FORTUNATO的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ELIZABETH A FORTUNATO', 18)}}的其他基金
HCMV infection downregulates nidogen 1 and myelin protein zero
HCMV 感染下调 nidogen 1 和髓磷脂蛋白 0
- 批准号:
10219059 - 财政年份:2018
- 资助金额:
$ 31.94万 - 项目类别:
HCMV infection downregulates nidogen 1 and myelin protein zero
HCMV 感染下调 nidogen 1 和髓磷脂蛋白 0
- 批准号:
9982196 - 财政年份:2018
- 资助金额:
$ 31.94万 - 项目类别:
HCMV infection downregulates nidogen 1 and myelin protein zero
HCMV 感染下调 nidogen 1 和髓磷脂蛋白 0
- 批准号:
9757691 - 财政年份:2018
- 资助金额:
$ 31.94万 - 项目类别:
HUMAN CYTOMEGALOVIRUS INTERACTIONS WITH CELLULAR P53
人类巨细胞病毒与细胞 P53 的相互作用
- 批准号:
7959728 - 财政年份:2009
- 资助金额:
$ 31.94万 - 项目类别:
HUMAN CYTOMEGALOVIRUS INTERACTIONS WITH CELLULAR P53
人类巨细胞病毒与细胞 P53 的相互作用
- 批准号:
7720366 - 财政年份:2008
- 资助金额:
$ 31.94万 - 项目类别:
HUMAN CYTOMEGALOVIRUS INTERACTIONS WITH CELLULAR P53
人类巨细胞病毒与细胞 P53 的相互作用
- 批准号:
7609814 - 财政年份:2007
- 资助金额:
$ 31.94万 - 项目类别:
HUMAN CYTOMEGALOVIRUS INTERACTIONS WITH CELLULAR P53
人类巨细胞病毒与细胞 P53 的相互作用
- 批准号:
7381184 - 财政年份:2006
- 资助金额:
$ 31.94万 - 项目类别:
Repair of HCMV-Induced DNA Damage in Infected Cells
修复受感染细胞中 HCMV 诱导的 DNA 损伤
- 批准号:
6827854 - 财政年份:2002
- 资助金额:
$ 31.94万 - 项目类别:
Repair of HCMV-Induced DNA Damage in Infected Cells
修复受感染细胞中 HCMV 诱导的 DNA 损伤
- 批准号:
8197095 - 财政年份:2002
- 资助金额:
$ 31.94万 - 项目类别:
Repair of HCMV-Induced DNA Damage in Infected Cells
修复受感染细胞中 HCMV 诱导的 DNA 损伤
- 批准号:
7783453 - 财政年份:2002
- 资助金额:
$ 31.94万 - 项目类别:
相似国自然基金
层出镰刀菌氮代谢调控因子AreA 介导伏马菌素 FB1 生物合成的作用机理
- 批准号:2021JJ40433
- 批准年份:2021
- 资助金额:0.0 万元
- 项目类别:省市级项目
寄主诱导梢腐病菌AreA和CYP51基因沉默增强甘蔗抗病性机制解析
- 批准号:32001603
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
AREA国际经济模型的移植.改进和应用
- 批准号:18870435
- 批准年份:1988
- 资助金额:2.0 万元
- 项目类别:面上项目
相似海外基金
Onboarding Rural Area Mathematics and Physical Science Scholars
农村地区数学和物理科学学者的入职
- 批准号:
2322614 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant
Point-scanning confocal with area detector
点扫描共焦与区域检测器
- 批准号:
534092360 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Major Research Instrumentation
TRACK-UK: Synthesized Census and Small Area Statistics for Transport and Energy
TRACK-UK:交通和能源综合人口普查和小区域统计
- 批准号:
ES/Z50290X/1 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Research Grant
Wide-area low-cost sustainable ocean temperature and velocity structure extraction using distributed fibre optic sensing within legacy seafloor cables
使用传统海底电缆中的分布式光纤传感进行广域低成本可持续海洋温度和速度结构提取
- 批准号:
NE/Y003365/1 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Research Grant
Collaborative Research: Scalable Manufacturing of Large-Area Thin Films of Metal-Organic Frameworks for Separations Applications
合作研究:用于分离应用的大面积金属有机框架薄膜的可扩展制造
- 批准号:
2326714 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant
Collaborative Research: Scalable Manufacturing of Large-Area Thin Films of Metal-Organic Frameworks for Separations Applications
合作研究:用于分离应用的大面积金属有机框架薄膜的可扩展制造
- 批准号:
2326713 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant
Unlicensed Low-Power Wide Area Networks for Location-based Services
用于基于位置的服务的免许可低功耗广域网
- 批准号:
24K20765 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
RAPID: Collaborative Research: Multifaceted Data Collection on the Aftermath of the March 26, 2024 Francis Scott Key Bridge Collapse in the DC-Maryland-Virginia Area
RAPID:协作研究:2024 年 3 月 26 日 DC-马里兰-弗吉尼亚地区 Francis Scott Key 大桥倒塌事故后果的多方面数据收集
- 批准号:
2427233 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant
RAPID: Collaborative Research: Multifaceted Data Collection on the Aftermath of the March 26, 2024 Francis Scott Key Bridge Collapse in the DC-Maryland-Virginia Area
RAPID:协作研究:2024 年 3 月 26 日 DC-马里兰-弗吉尼亚地区 Francis Scott Key 大桥倒塌事故后果的多方面数据收集
- 批准号:
2427232 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant
RAPID: Collaborative Research: Multifaceted Data Collection on the Aftermath of the March 26, 2024 Francis Scott Key Bridge Collapse in the DC-Maryland-Virginia Area
RAPID:协作研究:2024 年 3 月 26 日 DC-马里兰-弗吉尼亚地区 Francis Scott Key 大桥倒塌事故后果的多方面数据收集
- 批准号:
2427231 - 财政年份:2024
- 资助金额:
$ 31.94万 - 项目类别:
Standard Grant