CAMKV Kinase Signaling in Neuroblastoma
神经母细胞瘤中的 CAMKV 激酶信号转导
基本信息
- 批准号:10436321
- 负责人:
- 金额:--
- 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:2020-08-15 至 2022-07-10
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelBiological MarkersCREB1 geneCa(2+)-Calmodulin Dependent Protein KinaseCalciumCell LineCell ProliferationCessation of lifeChemoresistanceChildClustered Regularly Interspaced Short Palindromic RepeatsDefectDevelopmentDiseaseDisease OutcomeDoseFamilyGoalsGrowthK 252aKnock-outKnockout MiceMYCN geneMalignant - descriptorMalignant Childhood NeoplasmMalignant NeoplasmsMediator of activation proteinMolecularNeuroblastomaOncogenicPatient-Focused OutcomesPediatric NeoplasmPhosphotransferasesPlayProtein-Serine-Threonine KinasesProteinsRecurrenceRefractoryRegimenRegulationResearchResearch ProposalsRoleSamplingSignal PathwaySignal TransductionSolid NeoplasmSomatic MutationStimulusTestingTherapeuticTransgenic MiceTransgenic ModelTransgenic OrganismsVesicleWorkXenograft procedurebasebiological heterogeneitychemotherapeutic agentclinical heterogeneityconditional knockoutdesignexperimental studyhigh riskin vivoinhibitorinnovationknock-downmembermouse developmentmouse modelneuroblastoma cellnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpre-clinicalscreeningsmall molecule inhibitortherapy designtranscription factortumortumor growthtumorigenesis
项目摘要
Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children. High-risk NB
remains an incurable disease. Since recurrent somatic mutations in NB occur with relative paucity,
dysregulation of oncogenic signal transduction may contribute to NB tumorigenesis. This proposal will pursue
that goal by defining the role of CaM kinase-like vesicle-associated (CAMKV) in NB development and
examining the therapeutic potential of CAMKV kinase inhibition for treating NB in mouse models. In our
preliminary studies, we have found that CAMKV, structurally a member of the calcium/calmodulin-dependent
protein kinase family, is quite specifically overexpressed in NB tumor samples, and its high expression predicts
poor patient outcome. Furthermore, CAMKV acts as an active CREB kinase in NB cells. Knockdown of
CAMKV expression caused a cell proliferation defect and decreased phospho-CREB level in the NB cell lines
tested. In addition, we identified K252a and OTSSP167 as CAMKV inhibitors that potently inhibited cell
proliferation of several NB cell lines in culture and tumor growth in the xenograft mouse model. Interestingly,
our recently generated Camkv knockout mice are viable and fertile.
Our long term goal is to develop novel targeted therapies for children with high-risk NB. The objective of
this application is to understand the role of CAMKV in NB tumor development and demonstrate the utility of
CAMKV as a biomarker and kinase target for NB therapy.The central hypothesis of this work is that CAMKV
plays an important role in NB development and is a molecular kinase target in NB. The proposed experiments
will test this hypothesis by dissecting the function of CAMKV signaling in NB cells and determining the effect of
CAMKV inhibition on NB tumor growth in xenograft mouse models. We will also use recently generated Camkv
knockout mice to define the role of CAMKV in NB development in the Th-MYCN transgenic mouse model. The
specific aims for this project are: 1) To determine the mechanism of CAMKV regulation and function in NB
cells; 2) To determine the role of CAMKV in NB development in tumor mouse models; 3) To determine the
therapeutic potential of CAMKV inhibition in vivo. This contribution is significant because it will demonstrate
the critical role of CAMKV kinase in NB development and prove that CAMKV kinase inhibition is a potential
strategy to treat NB and overcome chemotherapy resistance in vivo. Furthermore, uncovering the regulation of
CAMKV kinase signaling will generate a blueprint for CAMKV-based design of treatment for refractory high-risk
NB. The proposed research is innovative since it is the first study to specifically uncover and target the
CAMKV signaling for designing NB therapeutics and to specifically study CAMKV inhibition by small molecule
inhibitors as a mechanism for overcoming chemotherapy resistance. This project will firmly establish CAMKV-
based therapy as a novel therapeutic strategy for refractory high-risk NB.
神经母细胞瘤是儿童最常见的颅内外恶性实体瘤。高风险的注
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)
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JIANHUA YANG其他文献
JIANHUA YANG的其他文献
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{{ truncateString('JIANHUA YANG', 18)}}的其他基金
DUSP26: A Novel Therapeutic Target in Neuroblastoma
DUSP26:神经母细胞瘤的新治疗靶点
- 批准号:
8423394 - 财政年份:2011
- 资助金额:
-- - 项目类别:
DUSP26: A Novel Therapeutic Target in Neuroblastoma
DUSP26:神经母细胞瘤的新治疗靶点
- 批准号:
8227975 - 财政年份:2011
- 资助金额:
-- - 项目类别:
DUSP26: A Novel Therapeutic Target in Neuroblastoma
DUSP26:神经母细胞瘤的新治疗靶点
- 批准号:
8625345 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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