Targeting Posttranslational Modifications in Breast Carcinogenesis
靶向乳腺癌发生中的翻译后修饰
基本信息
- 批准号:10523396
- 负责人:
- 金额:$ 46.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalADP ribosylationAffectApoptosisBRCA1 geneBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast Cancer therapyBreast CarcinogenesisCell divisionCellsChromatinComputer ModelsCryoelectron MicroscopyDNA DamageDNA RepairDNA damage checkpointDataDevelopmentERBB2 geneEndocrineExhibitsGKLF proteinGenerationsGenetic TranscriptionGenome StabilityGenomic InstabilityGoalsHumanImmunohistochemistryImpairmentKnock-inMaintenanceMalignant - descriptorMammary NeoplasmsMammary TumorigenesisMediatingModelingMolecularNeoplasm MetastasisOncogenicOrganoidsPathologicPhysiologicalPlayPoly(ADP-ribose) PolymerasesPost-Translational Protein ProcessingPrognosisRNA InterferenceRoleSignal TransductionStructureTestingThe Cancer Genome AtlasTherapeutic InterventionTranscriptional RegulationWorkbasecarcinogenesisclinically relevantdrug sensitivitygenome integrityin vivoinhibitormalignant breast neoplasmnovelnovel strategiespatient derived xenograft modelprotein complexrecruitresponsesmall molecular inhibitorsmall molecule inhibitorsynergismtargeted treatmenttriple-negative invasive breast carcinomatumortumor initiationtumor progressiontumorigenesis
项目摘要
Targeting Posttranslational Modifications in Breast Cancer
Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2-
targeted therapies. While the newly approved PARP inhibitors (PARPi) such as olaparib and talazoparib provide
a glint of hope to the approximately 15-20% of TNBC patients with BRCA1-deficiency, the need for a novel
strategy that could benefit the remaining 80-85% BRCA1-proficient TNBC patients is urgent and significant. The
goal of this project is to determine the impact of interplay between Krüppel-like factor 4 (KLF4) and poly-ADP-
ribose polymerase 1 (PARP1) in breast tumor progression and metastasis, and further develop a small molecule
inhibitor of KLF4 that synergizes with PARPi for anti-TNBC treatment. This proposal is based on our original
discovery that KLF4 acts as a critical signaling node in mediating DNA damage response (DDR)/DNA repair,
wherein the Poly-(ADP-ribosyl)ation (PARylation) of KLF4 by PARP1 dictates the chromatin recruitment for KLF4
that, in turn, governs KLF4 transcriptional function with respect to the maintenance of genome stability, tumor
progression/metastasis and drug sensitivity in breast cancer. These findings led to our central hypothesis that
dysregulation of KLF4 by PARP1 results in genome instability and tumor promotes progression/metastasis, and
blockade of KLF4 by newly developed KLF4 inhibitor synergizes PARPi for efficient killing of TNBC cells. Three
specific aims are proposed to elucidate the importance and mechanisms regulating KLF4 by PARP1: (1) To
determine the mechanism by which PARP1 regulates KLF4-mediated genome stability and carcinogenesis
through orchestrating the recruitment of KLF4 to chromatin; (2) To determine the physiological and clinical
relevance of KLF4 PARylation in breast tumor progression/metastasis; and (3) To validate the therapeutic
intervention of KLF4 inhibitor in synergizing with olaparib/talazoparib in anti-TNBC treatment using human breast
tumor organoid and patient-derived xenografts (PDXs).
!
!
!
靶向乳腺癌翻译后修饰
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 }}
Yong Wan其他文献
Yong Wan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('Yong Wan', 18)}}的其他基金
Targeting posttranslational modifications of CD73 in TNBCs
针对 TNBC 中 CD73 的翻译后修饰
- 批准号:
10359179 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy
靶向 B7-H4 的翻译后修饰在癌发生和治疗中的作用
- 批准号:
10361572 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting Posttranslational Modifications in Breast Carcinogenesis
靶向乳腺癌发生中的翻译后修饰
- 批准号:
10365966 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy
靶向 B7-H4 的翻译后修饰在癌发生和治疗中的作用
- 批准号:
10523400 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting posttranslational modifications of CD73 in TNBCs
针对 TNBC 中 CD73 的翻译后修饰
- 批准号:
10184613 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy
靶向 B7-H4 的翻译后修饰在癌发生和治疗中的作用
- 批准号:
10181635 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Interplay between ER and TGF-b in carcinogenesis
ER 和 TGF-b 在致癌过程中的相互作用
- 批准号:
10523253 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Targeting posttranslational modifications of CD73 in TNBCs
针对 TNBC 中 CD73 的翻译后修饰
- 批准号:
10523388 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Interplay between ER and TGF-b in carcinogenesis
ER 和 TGF-b 在致癌过程中的相互作用
- 批准号:
9655714 - 财政年份:2016
- 资助金额:
$ 46.22万 - 项目类别:
Targeting interplay between KLF4 and PRMT5 in carcinogenesis
靶向 KLF4 和 PRMT5 在致癌作用中的相互作用
- 批准号:
9977693 - 财政年份:2016
- 资助金额:
$ 46.22万 - 项目类别:
相似海外基金
Control of genomic integrity and virulence of Aspergillus fumigatus by ADP-ribosylation.
通过 ADP-核糖基化控制烟曲霉的基因组完整性和毒力。
- 批准号:
MR/X007472/1 - 财政年份:2023
- 资助金额:
$ 46.22万 - 项目类别:
Fellowship
Understanding the impact of DNA ADP-ribosylation on telomere function in cancer cells
了解 DNA ADP-核糖基化对癌细胞端粒功能的影响
- 批准号:
10751121 - 财政年份:2023
- 资助金额:
$ 46.22万 - 项目类别:
Composition and function of telomeric multi-protein complexes and their regulation by ADP-ribosylation
端粒多蛋白复合物的组成和功能及其ADP-核糖基化的调节
- 批准号:
2748032 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
Studentship
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
- 批准号:
10524783 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
Regulation of DNA repair by histone ADP-ribosylation
组蛋白 ADP 核糖基化调节 DNA 修复
- 批准号:
MR/W017350/1 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
Research Grant
Regulation and function of site-specific protein poly-ADP-ribosylation
位点特异性蛋白质聚 ADP 核糖基化的调控和功能
- 批准号:
10668492 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
ADP-ribosylation of DNA in Mycobacterium tuberculosis
结核分枝杆菌 DNA 的 ADP-核糖基化
- 批准号:
BB/W016613/1 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
Research Grant
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
- 批准号:
10610165 - 财政年份:2022
- 资助金额:
$ 46.22万 - 项目类别:
A Chemical Footprinting Approach towards Poly-ADP-Ribosylation-regulated Biomolecular Condensation
聚 ADP 核糖基化调节生物分子缩合的化学足迹方法
- 批准号:
10389853 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别:
Role of Transcription Factor ADP-ribosylation in Breast Cancer Biology
转录因子 ADP-核糖基化在乳腺癌生物学中的作用
- 批准号:
10593900 - 财政年份:2021
- 资助金额:
$ 46.22万 - 项目类别: