UCHL5 as a regulator and therapeutic target in metastatic melanoma
UCHL5 作为转移性黑色素瘤的调节剂和治疗靶点
基本信息
- 批准号:10225375
- 负责人:
- 金额:$ 41.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqActinsAnimal ModelAutomobile DrivingBiologicalBiological AssayCell LineCellsCessation of lifeChIP-seqCharacteristicsChemicalsChromatinChromatin LoopChromatin Remodeling FactorComplexCytoskeletonDNA MethylationDataDiseaseElementsEnhancersEnvironmentEnzymesEpigenetic ProcessEventF-ActinFDA approvedFelis catusFilopodiaG ActinGene ExpressionGenesGeneticGenetic TranscriptionGrowthHigher Order Chromatin StructureHumanHydrolaseImageKnockout MiceLIMK1 geneMalignant NeoplasmsMediatingMelanoma CellMetastatic MelanomaMetastatic toModelingNeoplasm MetastasisNucleosomesOncogenesPathway interactionsPatientsPharmacologic SubstancePhenotypePhosphoproteinsPolycombPositioning AttributePre-Clinical ModelProcessProteinsRegulationResearch PersonnelRoleSignal TransductionStructureTechnologyTestingTherapeuticTransgenic AnimalsUbiquitinValidationWorkWorld HealthXenograft ModelYY1 Transcription Factorbasecell motilitychromatin modificationcofilindepolymerizationdriving forceepigenomeepigenomicsepithelial to mesenchymal transitionexperimental studyfollow-upgain of functionin vivoinhibitor/antagonistinsightknock-downmelanomamembernoveloverexpressionpre-clinicalpromoterstandard of carestem cellstherapeutic targettranscriptomeubiquitin C-terminal hydrolase
项目摘要
Melanoma is a major world health problem with most deaths occurring due to metastatic
spread of the disease. Although genetic basis of melanoma formation has been well established
whether metastatic progression of melanoma is driven by genetic or epigenetic events remains
unclear. With a hypothesis that epigenetic events may be a key driving force for metastatic
progression, we performed an in vivo gain-of-function screen that identified 10 epigenetic
regulators as drivers of melanoma metastasis. In this proposal, we focus on one of the top hits -
UCHL5 - which is a deubiquitinase and a mammalian specific subunit of Ino80 chromatin
remodeling complex. Using in vitro and in vivo validation experiments, we have verified role of
UCHL5 in promoting melanoma invasion and metastasis. Importantly, our preliminary studies
show that UCHL5 involves its deubiquitinase activity as well as its association with Ino80 in
promotion of invasion. In addition, we find that UCHL5 may regulate important pro-metastatic
pathways such as RhoA-LIMK-Cofilin and SLIT-ROBO signaling via direct regulation of
ARHGAP29 and SLIT2 respectively. Therefore, the objective of this proposal is to examine the
contribution of UCHL5 and its regulation of epigenome reprogramming in driving melanoma
metastasis. In the first aim, we propose to characterize UCHL5 mediated epigenome
reprogramming using human melanoma cultures in conjunction with animal models and cutting-
edge epigenomic technologies. We will assess dynamics of nucleosome position and
reprogramming of superenhancer elements by UCHL5 and assess contribution of Ino80 as well
as YAP1, which we have identified as a novel interactor of UCHL5. In the second aim, we will
study signaling events downstream of UCHL5 with a focus on ARHGAP29 mediated regulation
of RhoA-LIMK-Cofilin signaling and actin dynamics. In the third aim, we propose to examine
therapeutic utility of UCHL5 inhibition alone as well as in combination with current standard-of-
care melanoma therapies in pre-clinical transgenic animal models of metastatic melanoma.
Together, our proposal will not only provide new insights into the epigenetic mechanisms driving
melanoma metastasis but also provide proof-of-concept evidence for use of UCHL5 inhibitors as
a therapeutic strategy in metastatic melanoma.
黑色素瘤是一个主要的世界健康问题,大多数死亡是由于转移
疾病的传播。尽管黑色素瘤形成的遗传基础已经得到很好的证实
黑色素瘤的转移性进展是由遗传事件还是表观遗传事件驱动的,目前尚不清楚
不清楚。假设表观遗传事件可能是转移的关键驱动力
进展,我们进行了体内功能获得筛查,确定了10个表观遗传学
调节剂是黑色素瘤转移的驱动因素。在这份提案中,我们将重点放在最热门的作品之一-
UCHL5-是一种脱泛素酶,也是INO80染色质的哺乳动物特异性亚基
重塑综合体。利用体外和体内验证实验,我们已经验证了
UCHL5促进黑色素瘤侵袭和转移。重要的是,我们的初步研究
表明UCHL5参与了其脱泛素酶活性以及它与INO80在
宣扬侵略。此外,我们发现UCHL5可能调节重要的促转移
RhoA-LIMK-cofilin和Sit-Robo等信号通路通过直接调节
ARHGAP29和SLIT2。因此,这项建议的目的是研究
UCHL5在黑色素瘤发生中的作用及其对表观基因组重编程的调控
转移。在第一个目标中,我们提出了UCHL5介导的表观基因组的特征
使用人类黑色素瘤培养物结合动物模型和切割进行重新编程-
边缘表观基因组技术。我们将评估核小体位置的动力学和
用UCHL5重新编程超级增强子元件并评估INO80的贡献
YAP1,我们已经确定它是UCHL5的一个新的相互作用元件。在第二个目标中,我们将
研究UCHL5下游信号事件,重点研究ARHGAP29介导的调控
RhoA-LIMK-cofilin信号和肌动蛋白动力学的研究。在第三个目标中,我们建议研究
UCHL5抑制剂单独及与现行标准联合应用的治疗效果
转移性黑色素瘤的临床前转基因动物模型的CARE治疗。
总之,我们的建议不仅将为表观遗传驱动机制提供新的见解
黑色素瘤转移,但也提供了UCHL5抑制剂用于
转移性黑色素瘤的治疗策略。
项目成果
期刊论文数量(0)
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Kunal Rai其他文献
Kunal Rai的其他文献
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{{ truncateString('Kunal Rai', 18)}}的其他基金
UCHL5 as a regulator and therapeutic target in metastatic melanoma
UCHL5 作为转移性黑色素瘤的调节剂和治疗靶点
- 批准号:
10402825 - 财政年份:2020
- 资助金额:
$ 41.15万 - 项目类别:
UCHL5 as a regulator and therapeutic target in metastatic melanoma
UCHL5 作为转移性黑色素瘤的调节剂和治疗靶点
- 批准号:
10616549 - 财政年份:2020
- 资助金额:
$ 41.15万 - 项目类别:
Role of UBR7, a novel H2BK120 E3 ubiquitin ligase, in suppression of breast cancer
UBR7(一种新型 H2BK120 E3 泛素连接酶)在抑制乳腺癌中的作用
- 批准号:
10371220 - 财政年份:2020
- 资助金额:
$ 41.15万 - 项目类别:
Role of UBR7, a novel H2BK120 E3 ubiquitin ligase, in suppression of breast cancer
UBR7(一种新型 H2BK120 E3 泛素连接酶)在抑制乳腺癌中的作用
- 批准号:
10594949 - 财政年份:2020
- 资助金额:
$ 41.15万 - 项目类别:
Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma
KMT2D 和异常增强子在调节黑色素瘤肿瘤微环境中的作用
- 批准号:
10463568 - 财政年份:2018
- 资助金额:
$ 41.15万 - 项目类别:
Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma
KMT2D 和异常增强子在调节黑色素瘤肿瘤微环境中的作用
- 批准号:
10219181 - 财政年份:2018
- 资助金额:
$ 41.15万 - 项目类别:
Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma
KMT2D 和异常增强子在调节黑色素瘤肿瘤微环境中的作用
- 批准号:
9751818 - 财政年份:2018
- 资助金额:
$ 41.15万 - 项目类别:
Role of KMT2D and aberrant enhancers in modulating tumor microenvironment in melanoma
KMT2D 和异常增强子在调节黑色素瘤肿瘤微环境中的作用
- 批准号:
9981689 - 财政年份:2018
- 资助金额:
$ 41.15万 - 项目类别:
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