RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
基本信息
- 批准号:10524771
- 负责人:
- 金额:$ 52.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-07 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAntimitotic AgentsAntineoplastic AgentsAntitumor ResponseAntsAreaBiological ModelsCRISPR interferenceCRISPR-mediated transcriptional activationCancer PatientCell LineChemoresistanceCisplatinClinicalCollectionCombined Modality TherapyCommunitiesComputer AnalysisCytotoxic agentDNA DamageDNA SequenceDNA-dependent protein kinaseDataData SetDefectDevelopmentDiagnosisDiseaseDisease ResistanceDrug resistanceEpitheliumExcisionFoundationsGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGoalsHematopoietic NeoplasmsHistologicHumanImmunotherapyIn VitroLaboratoriesLimesLinkMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediatingMedicalMessenger RNAMicrotubulesMitoticMolecularMutationNon-Small-Cell Lung CarcinomaOperative Surgical ProceduresOutcome StudyOvarian CarcinomaPaclitaxelPathway interactionsPatientsPharmaceutical PreparationsPhosphorylation SitePhosphotransferasesPlatinumPlatinum CompoundsPoly(ADP-ribose) Polymerase InhibitorProtein KinaseProteinsRNA BindingRNA ProcessingRNA StabilityRNA interference screenRNA-Binding ProteinsRecurrenceRegulationRelapseResearch PersonnelResistanceRoleSerousSignal PathwaySolid NeoplasmTP53 geneTechnologyTherapeuticTreatment ProtocolsUnited StatesWomanWorkXenograft ModelXenograft procedurebioinformatics pipelinebrca genecancer cellcancer drug resistancecancer therapychemotherapycytotoxicdifferential expressionexperimental studyfrontiergenome wide screengenome-widehomologous recombinationimprovedin vivomolecular targeted therapiesmouse modelmutantovarian neoplasmp38 Mitogen Activated Protein Kinasepatient derived xenograft modelposttranscriptionalpreventprotein functionrecombinational repairresistance mechanismresistance mutationresponsescreeningstandard of caresuccesstaxanetherapeutic developmenttherapy resistanttranscriptome sequencingtumorupstream kinaseweb-based tool
项目摘要
Project Summary
Ovarian carcinoma is the fifth deadliest cancer among women in the United States. In spite of advances
in surgical resection and platinum-taxane combination therapy over the past several decades, cure rates
remain relatively low (~30%) and a majority of women diagnosed with advanced ovarian cancer will die with
drug-resistant disease within 5 years. The long-term goal of this project, “RNA-Binding Proteins as Molecular
Integrators that Control the Response of HGSOC to Anti-Cancer Therapies”, is to identify specific RNA-binding
proteins that, together with their upstream protein kinase regulators, control the resistance and sensitivity of
high-grade serous ovarian cancers to these clinically used first line anti-cancer therapies. The project involves:
(1) a detailed computational analysis that queries pre-existing publically available RNA expression data using
RNA-BP recognition motifs to identify specific RNA binding proteins whose mRNA targets are up- or down-
regulated in ovarian cancer patients with chemo-sensitive versus chemo-resistant tumors; and (2) an
independent CRISPR-interference and CRISPR-activation genome-wide screen for RNA-BPs whose
manipulation alters the resistance and sensitivity of ovarian cancer cells to platinum and taxane agents in vitro,
and in vivo using cell line xenografts and human PDX ovarian cancer mouse models. The RNA-BPs identify
by these two complimentary approaches, together with a collection of RNA-BPs that we have already identified
in previous experiments and preliminary data, are then directly validated for their effects on drug resistance in
these model systems, and the identity of their bound RNAs and their effects on gene expression determined
using CLIP technologies and RNA-Seq. In selected cases the importance of specific phosphorylation sites on
RNA-BP function is examined to further elucidate the molecular basis for anti-cancer drug resistance through
pathway-specific regulation of RNA-BP action. The project builds on a broad foundation of expertise and
related work from all of the co-Investigators laboratories. Expected outcomes from the studies include the
identification of specific RNA-BPs and upstream regulatory kinase pathways whose targeting can prevent or
reverse the resistance of ovarian cancers to current clinically used front-lime therapeutics; the elucidation of
new molecular circuits that control gene expression in cancers after chemotherapy treatment; and the creation
of a suite of web-based tools available to the entire scientific community that can be used to query any set of
differentially expressed genes for RNA-BP-based regulation, particularly in a form that is optimized for analysis
of new and existing cancer patient RNA expression datasets.
项目总结
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.
- DOI:10.3389/fimmu.2020.607891
- 发表时间:2020
- 期刊:
- 影响因子:7.3
- 作者:Suarez-Lopez L;Kong YW;Sriram G;Patterson JC;Rosenberg S;Morandell S;Haigis KM;Yaffe MB
- 通讯作者:Yaffe MB
Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.
功能基因组学揭示了胃癌治疗中药物协同作用的脱靶依赖性。
- DOI:10.1101/2023.10.07.561351
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Leylek,Ozen;Honeywell,MeganE;Lee,MichaelJ;Hemann,MichaelT;Ozcan,Gulnihal
- 通讯作者:Ozcan,Gulnihal
Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
- DOI:10.1038/s41467-021-26407-4
- 发表时间:2021-10-28
- 期刊:
- 影响因子:16.6
- 作者:Bent EH;Millán-Barea LR;Zhuang I;Goulet DR;Fröse J;Hemann MT
- 通讯作者:Hemann MT
Multi-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks.
- DOI:10.1038/s41467-022-32743-w
- 发表时间:2022-09-08
- 期刊:
- 影响因子:16.6
- 作者:
- 通讯作者:
Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.
早期免疫变化支持 CDH1 驱动的遗传性弥漫性胃癌中印戒细胞休眠。
- DOI:10.1158/1541-7786.mcr-23-0122
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Green,BenjaminL;Gamble,LaurenA;Diggs,LaurenceP;Nousome,Darryl;Patterson,JesseC;Joughin,BrianA;Gasmi,Billel;Lux,StephanieC;Samaranayake,SarahG;Miettinen,Markku;Quezado,Martha;Hernandez,JonathanM;Yaffe,MichaelB;Davis,Jere
- 通讯作者:Davis,Jere
{{
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 }}
CHRISTOPHER B BURGE其他文献
CHRISTOPHER B BURGE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('CHRISTOPHER B BURGE', 18)}}的其他基金
Regulation and Function of Alternative mRNA Isoform Expression in Mammals
哺乳动物中替代 mRNA 同工型表达的调节和功能
- 批准号:
10540339 - 财政年份:2021
- 资助金额:
$ 52.58万 - 项目类别:
Regulation and Function of Alternative mRNA Isoform Expression in Mammals
哺乳动物中替代 mRNA 同工型表达的调节和功能
- 批准号:
10323056 - 财政年份:2021
- 资助金额:
$ 52.58万 - 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
- 批准号:
10054974 - 财政年份:2018
- 资助金额:
$ 52.58万 - 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
- 批准号:
10305607 - 财政年份:2018
- 资助金额:
$ 52.58万 - 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
- 批准号:
8684871 - 财政年份:2014
- 资助金额:
$ 52.58万 - 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
- 批准号:
8852097 - 财政年份:2014
- 资助金额:
$ 52.58万 - 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
- 批准号:
8310598 - 财政年份:2012
- 资助金额:
$ 52.58万 - 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
- 批准号:
8628858 - 财政年份:2012
- 资助金额:
$ 52.58万 - 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
- 批准号:
8463015 - 财政年份:2012
- 资助金额:
$ 52.58万 - 项目类别:
相似海外基金
A novel bioassay system for antimitotic agents using unicellular organisms
使用单细胞生物体的新型抗有丝分裂剂生物测定系统
- 批准号:
25560416 - 财政年份:2013
- 资助金额:
$ 52.58万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
APOPTOSIS-INDUCING ANTIMITOTIC AGENTS FOR CANCER THERAPY
用于癌症治疗的细胞凋亡诱导抗有丝分裂剂
- 批准号:
6298857 - 财政年份:2001
- 资助金额:
$ 52.58万 - 项目类别:
STUDIES ON THE ANTIMITOTIC AGENTS-TUBULIN INTERACTION AND DRUG DESIGN
抗有丝分裂剂-微管蛋白相互作用及药物设计的研究
- 批准号:
08407070 - 财政年份:1996
- 资助金额:
$ 52.58万 - 项目类别:
Grant-in-Aid for Scientific Research (A)