Investigate role of microRNA cluster 183-96-182 in DNA repair and radiosensitivit
研究 microRNA 簇 183-96-182 在 DNA 修复和放射敏感性中的作用
基本信息
- 批准号:8434262
- 负责人:
- 金额:$ 33.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-02-01 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlgorithmsApoptosisAttenuatedBRCA1 geneBiochemicalBioinformaticsBiological AssayBlood CellsBreastCancer BiologyCell DeathCell Differentiation processCell LineCellsChromosome BreakageChronic Lymphocytic LeukemiaClinicalComet AssayDNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA repair proteinFunctional RNAGastrointestinal tract structureGene ExpressionGene TargetingGoalsHematopoieticHousingIn VitroInterphase CellIonizing radiationKidneyLungMalignant NeoplasmsMeasuresMediatingMessenger RNAMicroRNAsMitoticMolecular ProfilingMonitorNeuraxisNonhomologous DNA End JoiningNormal CellOvaryPathway interactionsPhenotypeProductionProstateProteinsPulsed-Field Gel ElectrophoresisRadiationRadiation ToleranceRadiation therapyReagentReporterResistanceResistance developmentRoleSpecificitySystemTranscriptTransformed Cell Lineattenuationcancer cellcancer therapychemotherapeutic agentcytotoxichomologous recombinationirradiationmelanomamemberneoplastic cellnoveloutcome forecastoverexpressionpublic health relevancerepairedresearch studyresponsetherapy resistanttumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant):
Radiation and chemotherapeutic agents eradicate tumors by inducing irreparable DNA damage. However, cancer cells often develop resistance to therapy by manipulating the DNA repair machinery. Conversely, a dividing cell constantly exposed to environmental and endogenous DNA damaging agents can transform into a tumor due to incorrect repair. Therefore the expression level of DNA repair proteins is critical both for cancer therapy and tumorigenesis. In our preliminary studies we have discovered a novel connection between a new class of gene expression regulators, microRNAs and DNA repair proteins. MicroRNAs (miRNAs) are small non-coding RNAs that typically dampen gene expression. There is accumulating evidence that miRNAs are mis-expressed in cancer cells. It is noteworthy that ectopic overexpression of miRNAs downregulating DNA repair proteins could sensitize cancer cells to radiation and other genotoxic reagents. Alternatively, tumors that delete these miRNAs may develop resistance to conventional cancer therapy. DNA repair is a 'house keeping' function, and micro-RNA mediated attenuation of DNA repair may appear counter intuitive. However, normal cells down modulate DNA repair in a terminally differentiated state where overall DNA repair is downregulated. Using the experimental system of in vitro hematopoietic cell differentiation, we have identified microRNAs (miRNAs), miR-24 and a polycistronic miRNA cluster including miRNAs (183, 96, 182), that are upregulated in terminally differentiated non-dividing cells but are rapidly down regulated in response to ionizing radiation (IR) in dividing cells. We hypothesize that in post-mitotic cells DNA damage induces apoptosis and miRNAs attenuate the DNA repair machinery promoting cell death. Conversely, in response to IR the miRNAs are downmodulated in dividing cells to accentuate the production of DNA repair proteins and boost the DNA damage response. In support of this contention, we observed, that miR-24, downregulates the expression of a key DSB repair protein, H2AX and impedes DSB repair in terminally differentiated blood cells. The miRNAs (182,183 and 96) that we propose to study have already been noted for aberrant expression in a variety of tumors. A direct effect of these miRNAs on cancer could be by dysregulation of the DNA repair machinery. Bioinformatic predictions suggest that several DNA repair genes, such as, BRCA1, ATR, XLF, etc. are targeted by the miRNAs-183, 96 and 182. Preliminary experiments validate the prediction that miR-182 regulates BRCA1. In Aim #1 we will use different computational, and biochemical strategies, to identify and validate DNA repair factors targeted by miRNAs-183, 96 and 182 in transformed cell lines and primary cells. In Aim #2 we will systematically study the effect of these miRNAs on DSB repair and determine their impact on each repair pathway. Finally we will evaluate the radiosensitivity of cancer cells expressing these miRNAs. There is limited understanding of the role of miRNAs in DNA repair and this study will address this issue and also elucidate the impact of miRNAs on radiotherapy.
描述(由申请人提供):
放射和化疗药物通过诱导不可修复的DNA损伤来根除肿瘤。然而,癌细胞往往通过操纵DNA修复机制而对治疗产生抵抗力。相反,不断暴露在环境和内源性DNA损伤剂下的分裂细胞可能会因为不正确的修复而转化为肿瘤。因此,DNA修复蛋白的表达水平对于癌症治疗和肿瘤发生都是至关重要的。在我们的初步研究中,我们发现了一类新的基因表达调控因子、microRNAs和DNA修复蛋白之间的新联系。MicroRNAs(MiRNAs)是一种小的非编码RNA,通常会抑制基因表达。越来越多的证据表明,miRNAs在癌细胞中错误表达。值得注意的是,异位过表达下调DNA修复蛋白的miRNAs可能会使癌细胞对辐射和其他遗传毒性试剂敏感。或者,缺失这些miRNAs的肿瘤可能会对传统的癌症治疗产生抗药性。DNA修复是一种“看家”功能,而微小RNA介导的DNA修复减弱可能看起来与直觉相反。然而,正常细胞在终末分化状态下下调DNA修复,其中整体DNA修复下调。利用体外造血细胞分化实验系统,我们鉴定了microRNAs(MiRNAs),miR-24和一个多顺反子miRNA簇,包括miRNAs(183,96,182),它们在终末分化的未分裂细胞中上调,但在分裂细胞中对电离辐射(IR)反应迅速下调。我们假设,在有丝分裂后细胞中,DNA损伤诱导细胞凋亡,而miRNAs减弱促进细胞死亡的DNA修复机制。相反,作为对IR的反应,miRNAs在分裂细胞时被下调,以增强DNA修复蛋白的产生,并增强DNA损伤反应。为了支持这一观点,我们观察到,miR-24下调了关键的DSB修复蛋白H2 AX的表达,并阻碍了终末分化血细胞中的DSB修复。我们计划研究的miRNAs(182,183和96)已经被注意到在各种肿瘤中异常表达。这些miRNAs对癌症的直接影响可能是通过DNA修复机制的失调。生物信息学预测表明,几个DNA修复基因,如BRCA1,ATR,XLF等是miRNAs-183,96和182的靶点。初步实验验证了miR-182调控BRCA1的预测。在目标1中,我们将使用不同的计算和生化策略来识别和验证在转化细胞系和原代细胞中由miRNAs-183、96和182靶向的DNA修复因子。在目标2中,我们将系统地研究这些miRNAs对DSB修复的影响,并确定它们对每条修复途径的影响。最后,我们将评估表达这些miRNAs的癌细胞的放射敏感性。目前对miRNAs在DNA修复中的作用了解有限,本研究将解决这一问题,并阐明miRNAs对放射治疗的影响。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Dipanjan Chowdhury其他文献
Dipanjan Chowdhury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('Dipanjan Chowdhury', 18)}}的其他基金
Elucidating the molecular mechanism and physiological relevance of TIRR mediated inhibition of p53
阐明 TIRR 介导的 p53 抑制的分子机制和生理相关性
- 批准号:
10464410 - 财政年份:2022
- 资助金额:
$ 33.11万 - 项目类别:
Elucidating the molecular mechanism and physiological relevance of TIRR mediated inhibition of p53
阐明 TIRR 介导的 p53 抑制的分子机制和生理相关性
- 批准号:
10657573 - 财政年份:2022
- 资助金额:
$ 33.11万 - 项目类别:
Investigating 53BP1 'dephosphorylation' as a critical determinant of PARP
研究 53BP1“去磷酸化”作为 PARP 的关键决定因素
- 批准号:
9310754 - 财政年份:2017
- 资助金额:
$ 33.11万 - 项目类别:
Serum microRNA as biomarker for radiation injury to lung and hematopoietic cells
血清 microRNA 作为肺和造血细胞辐射损伤的生物标志物
- 批准号:
8486393 - 财政年份:2012
- 资助金额:
$ 33.11万 - 项目类别:
Serum microRNA as biomarker for radiation injury to lung and hematopoietic cells
血清 microRNA 作为肺和造血细胞辐射损伤的生物标志物
- 批准号:
8370333 - 财政年份:2012
- 资助金额:
$ 33.11万 - 项目类别:
Serum microRNA as biomarker for radiation injury to lung and hematopoietic cells
血清 microRNA 作为肺和造血细胞辐射损伤的生物标志物
- 批准号:
8660032 - 财政年份:2012
- 资助金额:
$ 33.11万 - 项目类别:
Serum microRNA as biomarker for radiation injury to lung and hematopoietic cells
血清 microRNA 作为肺和造血细胞辐射损伤的生物标志物
- 批准号:
9064076 - 财政年份:2012
- 资助金额:
$ 33.11万 - 项目类别:
Investigate role of microRNA cluster 183-96-182 in DNA repair and radiosensitivit
研究 microRNA 簇 183-96-182 在 DNA 修复和放射敏感性中的作用
- 批准号:
7766538 - 财政年份:2010
- 资助金额:
$ 33.11万 - 项目类别:
Investigate role of microRNA cluster 183-96-182 in DNA repair and radiosensitivit
研究 microRNA 簇 183-96-182 在 DNA 修复和放射敏感性中的作用
- 批准号:
8606431 - 财政年份:2010
- 资助金额:
$ 33.11万 - 项目类别:
相似海外基金
DMS-EPSRC: Asymptotic Analysis of Online Training Algorithms in Machine Learning: Recurrent, Graphical, and Deep Neural Networks
DMS-EPSRC:机器学习中在线训练算法的渐近分析:循环、图形和深度神经网络
- 批准号:
EP/Y029089/1 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Research Grant
CAREER: Blessing of Nonconvexity in Machine Learning - Landscape Analysis and Efficient Algorithms
职业:机器学习中非凸性的祝福 - 景观分析和高效算法
- 批准号:
2337776 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Continuing Grant
CAREER: From Dynamic Algorithms to Fast Optimization and Back
职业:从动态算法到快速优化并返回
- 批准号:
2338816 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Continuing Grant
CAREER: Structured Minimax Optimization: Theory, Algorithms, and Applications in Robust Learning
职业:结构化极小极大优化:稳健学习中的理论、算法和应用
- 批准号:
2338846 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Continuing Grant
CRII: SaTC: Reliable Hardware Architectures Against Side-Channel Attacks for Post-Quantum Cryptographic Algorithms
CRII:SaTC:针对后量子密码算法的侧通道攻击的可靠硬件架构
- 批准号:
2348261 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Standard Grant
CRII: AF: The Impact of Knowledge on the Performance of Distributed Algorithms
CRII:AF:知识对分布式算法性能的影响
- 批准号:
2348346 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Standard Grant
CRII: CSR: From Bloom Filters to Noise Reduction Streaming Algorithms
CRII:CSR:从布隆过滤器到降噪流算法
- 批准号:
2348457 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Standard Grant
EAGER: Search-Accelerated Markov Chain Monte Carlo Algorithms for Bayesian Neural Networks and Trillion-Dimensional Problems
EAGER:贝叶斯神经网络和万亿维问题的搜索加速马尔可夫链蒙特卡罗算法
- 批准号:
2404989 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Standard Grant
CAREER: Efficient Algorithms for Modern Computer Architecture
职业:现代计算机架构的高效算法
- 批准号:
2339310 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Continuing Grant
CAREER: Improving Real-world Performance of AI Biosignal Algorithms
职业:提高人工智能生物信号算法的实际性能
- 批准号:
2339669 - 财政年份:2024
- 资助金额:
$ 33.11万 - 项目类别:
Continuing Grant