Chemo-mediated transcriptional reprogramming in ovarian cancer
Chemo-mediated transcriptional reprogramming in ovarian cancer
批准号:
10346704
负责人:
Mazhar Adli
金额:
$47.23万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-23 至 2027-08-31
关键词:
ATAC-seqAcuteArchitectureBiologyCarboplatinCarcinomaCellsCessation of lifeChemoresistanceChromatinCisplatinClinicalClustered Regularly Interspaced Short Palindromic RepeatsDNA DamageDNA RepairDNA Sequence AlterationDataDoseEnhancersEpigenetic ProcessGatekeepingGene ExpressionGenesGeneticGenetic TranscriptionGenomeGenomicsGoalsGrowthImmunocompetentIn VitroMalignant - descriptorMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediatingModelingMolecularNon-MalignantOperative Surgical ProceduresOvarian Serous AdenocarcinomaPathway interactionsPatientsPlatinumPlayPopulationPrimary NeoplasmPrognosisPublishingRecurrenceRelapseRepressionResearchResistanceRoleSamplingSerousTechnologyTestingTherapeuticTumor DebulkingTumor ImmunityTumor TissueUp-RegulationWorkarginine methyltransferasebasecancer cellcancer subtypescancer therapychemotherapyclinically relevantcohortcombinatorialcomparativeepigenomeepigenomicsgenome editinggenome-wideimprovedin vivoinsightmortalitynon-geneticnovelnovel therapeutic interventionprogrammed cell death ligand 1programsresponsescreeningsingle-cell RNA sequencingstem-like celltherapeutic targettherapeutically effectivetooltranscription factortranscriptional reprogrammingtranscriptometranscriptomicstumor
中文摘要
摘要
高级别浆液性癌(HGSC)是最具侵袭性的OC亚型,占OC相关亚型的80%
死亡。铂耐药的迅速出现是导致这种死亡的主要原因。尽管最初
手术加化疗后,80%的患者肿瘤复发,并迅速产生化疗耐药。
尽管很少有基因突变与化疗耐药有关,但在很大一部分肿瘤中,驱动因素
化疗耐药的快速出现的原因尚不清楚。在这里,我们提出了非遗传机制在
在高级别浆液性卵巢癌中调节细胞向耐药状态转变的重要部分。我们
将从全球转录重编程的角度解决铂耐药的出现。我们的
已发表的初步研究结果支持铂耐药产生于治疗诱导的假说。
种群水平的表观基因组和转录重编程。通过对表观基因组的整合分析
和多个对顺铂耐药的同基因细胞的转录本,我们鉴定了耐药状态特异性
超级增强子及其靶向转录因子网络(TFN)。第一个目标使用了尖端技术
基因组作图和操作技术,包括单细胞水平的CRISPR扰动,随后是
转录组分析,以确定哪些TF和TF-组合是将幼稚细胞重新编程为
抵抗状态。第二个目标是研究一种新的组合靶标,以实现合成杀伤力
HGSOC中的卡铂。这项提案的发现将为关键字的作用提供新的机械性见解
调控卵巢癌铂耐药的转录因子网络。
英文摘要
Abstract
High-grade serous carcinoma (HGSC) is the most aggressive OC subtype that accounts for 80% of OC-related
deaths. Rapid emergence of platinum (Pt)-resistance is the main reason for this mortality. Despite initial
response to surgery plus chemotherapy, tumors relapse and rapidly become chemoresistant in 80% of patients.
Although few genetic mutations have been associated with chemoresistance, in a large fraction of tumors, drivers
of the chemoresistance's rapid emergence are unknown. Here we propose that non-genetic mechanisms play
an important part in regulating cellular transition to a resistant state in high grade serous ovarian cancer. We
will tackle the emergence of Pt resistance from a global transcriptional reprogramming point of view. Our
published and preliminary findings support the hypothesis that Pt resistance emerges from therapy-induced
population-level epigenomic and transcriptional reprogramming. Through integrative analysis of epigenomes
and transcriptomes of multiple naïve and cisplatin-resistant isogenic cells, we identified resistant-state specific
super-enhancers and their target transcription factor networks (TFN). The first aim employs cutting edge
genomic mapping and manipulation technologies including single cell-level CRISPR-perturbations followed by
transcriptome profiling to identify which TFs and TF-combinations are necessary to reprogram naïve cells into
the resistant state. The second aim investigates a novel combinatorial target to achieve synthetic lethality with
carboplatin in HGSOC. The findings from this proposal will provide new mechanistic insight into the role of key
transcription factor network that govern platinum resistance in ovarian cancer.
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Chemo-mediated transcriptional reprogramming in ovarian cancer
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批准号:10709477
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项目类别:
-
资助金额:$45.24万
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财政年份:2022
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负责人:Mazhar Adli
-
依托单位:
Molecular and cellular characterization of essential human genes.
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批准号:10708906
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项目类别:
-
资助金额:$163.13万
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财政年份:2022
-
负责人:Mazhar Adli
-
依托单位:
Molecular and cellular characterization of essential human genes.
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批准号:10517781
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项目类别:
-
资助金额:$166.98万
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财政年份:2022
-
负责人:Mazhar Adli
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依托单位:
Identifying the Drivers and Targeting Chemo Resistance in Ovarian Cancer
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批准号:10166791
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项目类别:
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资助金额:$41.39万
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财政年份:2017
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负责人:Mazhar Adli
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依托单位:
Identifying the Drivers and Targeting Chemo Resistance in Ovarian Cancer
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批准号:9330488
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项目类别:
-
资助金额:$42.92万
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财政年份:2017
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负责人:Mazhar Adli
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依托单位:
海外基金