Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets
阐明神经纤维瘤病的表观遗传景观和治疗靶点的开发
基本信息
- 批准号:10473771
- 负责人:
- 金额:$ 42.32万
- 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:2021-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcoustic NerveAnimal ModelAntineoplastic AgentsBindingBromodomainCell Differentiation processCell ProliferationCellsChIP-seqClinical TrialsCodeContact InhibitionDataDevelopmentDiseaseDown-RegulationEnsureEpendymomaEpigenetic ProcessFamilyFrequenciesGenesGenetic TranscriptionGenomicsGerm-Line MutationGoalsGrowthHereditary DiseaseHistone AcetylationHistonesImpairmentInheritedLoss of HeterozygosityLysineMalignant NeoplasmsMediatingMesotheliomaModalityModelingMolecularMonomeric GTP-Binding ProteinsMutateMutationNervous System NeoplasmsNervous system structureNeurilemmomaNeurofibromatosesNeurofibromatosis 2Neurofibromin 2Normal CellOutputPathway interactionsPatientsPharmaceutical PreparationsPhase I Clinical TrialsPlayProteinsReaderReceptor Protein-Tyrosine KinasesRegulationResolutionRoleSchwann CellsSignal PathwaySignal Transduction PathwayTechnologyTertiary Protein StructureTherapeuticTherapeutic InterventionTranscriptional RegulationTranslatingTumor Suppressor Genesbasecancer cellcancer typeepigenomicsin vivoinhibitorinterestmeningiomaneoplastic cellpreventprogramsprotein functionras Proteinsresearch clinical testingsmall moleculesmall molecule inhibitorsynergismtargeted treatmenttherapeutic developmenttherapeutic targettranscriptome sequencingtumortumor growthtumorigenesisvirtual
项目摘要
Neurofibromatosis type 2 (NF2) is an inherited disorder caused by germ line mutations of the NF2 tumor
suppressor gene and is characterized by development of schwannomas of the VIIIth cranial nerve. Merlin, the
product of the NF2 gene, is also inactivated to a significant extent in sporadic schwannomas, meningioma,
ependymoma and mesothelioma. In spite of progress made in the understanding of the disease over the past
several years, this has not yet translated into therapies. Thus, there is an urgent and unmet need to develop
therapeutic options for NF2 patients. At a molecular level, Merlin has been shown to function as a key regulator
of multiple signal transduction pathways including those regulated by small G-proteins and the Hippo/YAP
pathway.
In an effort to identify therapeutic vulnerabilities in NF2-deficient tumors, we assessed the activity of the BET
(Bromodomain and Extra-Terminal domain) protein inhibitors NF2-null Schwann cells. The BET proteins are
characterized by the presence of two tandem bromodomains and an extra-terminal domain. The bromodomains
can specifically bind acetylated lysine residues on histones, serving as epigenetic readers that decipher the
histone acetylation code. Our preliminary data indicate that BET inhibition suppresses the proliferation of NF2-
null Schwann and schwannoma cells in culture and tumor growth in vivo, and that this is mediated through
inhibition of bromodomain protein 4 (BRD4). Preliminary data indicates that the effects of BRD4 are mediated to
a significant extent via regulation of YAP. Importantly, we recently demonstrated that YAP is required for the
accelerated proliferation of NF2-deficient Schwann cells and tumorigenesis. The goals of this proposal are to
identify the essential functions of BET proteins in Schwann cells and determine whether BET inhibition is a
therapeutic approach that should be further developed as a treatment modality for NF2.
2型神经纤维瘤病(NF2)是一种由NF2肿瘤种系突变引起的遗传性疾病
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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JOSEPH KISSIL其他文献
JOSEPH KISSIL的其他文献
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{{ truncateString('JOSEPH KISSIL', 18)}}的其他基金
Employing functionalized fragment libraries to identify therapeutic agents for neurofibromatosis type 2
利用功能化片段库来鉴定 2 型神经纤维瘤病的治疗药物
- 批准号:
10401628 - 财政年份:2021
- 资助金额:
$ 42.32万 - 项目类别:
Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets
阐明神经纤维瘤病的表观遗传景观和治疗靶点的开发
- 批准号:
10680527 - 财政年份:2021
- 资助金额:
$ 42.32万 - 项目类别:
Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets
阐明神经纤维瘤病的表观遗传景观和治疗靶点的开发
- 批准号:
10211400 - 财政年份:2021
- 资助金额:
$ 42.32万 - 项目类别:
Employing functionalized fragment libraries to identify therapeutic agents for neurofibromatosis type 2
利用功能化片段库来鉴定 2 型神经纤维瘤病的治疗药物
- 批准号:
10704416 - 财政年份:2021
- 资助金额:
$ 42.32万 - 项目类别:
CARM1-mediated regulation of YAP1 as a therapeutic target in lung cancer
CARM1 介导的 YAP1 调节作为肺癌的治疗靶点
- 批准号:
10391561 - 财政年份:2020
- 资助金额:
$ 42.32万 - 项目类别:
CARM1-mediated regulation of YAP1 as a therapeutic target in lung cancer
CARM1 介导的 YAP1 调节作为肺癌的治疗靶点
- 批准号:
10613467 - 财政年份:2020
- 资助金额:
$ 42.32万 - 项目类别:
Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets
阐明神经纤维瘤病的表观遗传景观和治疗靶点的开发
- 批准号:
10201375 - 财政年份:2020
- 资助金额:
$ 42.32万 - 项目类别:














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