ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS
复制应激在 MYC 依赖性淋巴细胞生成过程中的作用
基本信息
- 批准号:8146177
- 负责人:
- 金额:$ 14.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-22 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive TransferAffectB-Cell LymphomasB-LymphocytesBiologicalBiological AssayBiologyCell ProliferationCellsCharacteristicsComplementary DNADNA DamageDNA biosynthesisDevelopmentDevelopment PlansDisciplineDiseaseEngineeringEnsureEnvironmentEpigenetic ProcessEventGene LibraryGenesGeneticGenetic TranscriptionGoalsGrowthHematopoietic stem cellsHumanIn VitroKnowledgeLesionLymphomaLymphomagenesisMalignant NeoplasmsMeasuresMentorsMolecularMusMutagenesisOncogene ActivationOncogenesOncogenicOpen Reading FramesOutcomePathway interactionsPhasePhenotypePhysiologicalProcessProteinsProto-OncogenesRelative (related person)Replication InitiationReporterResearchResearch Project GrantsRoleScreening procedureStressSystemSystems BiologyTechniquesTestingTissuesTrainingTranscriptional RegulationTransgenic MiceValidationVariantabstractingbasec-myc Genescancer initiationcancer therapycancer typecareer developmentcell transformationcopinghigh throughput technologyin vivoinsightinterestmouse modelmutantneoplastic cellnew therapeutic targetnoveloverexpressionpublic health relevanceresponseskillssuccesstherapeutic targettumortumor initiationtumor progressiontumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): Deregulated expression of the c-Myc protooncogene is a frequent requisite for the development of many human cancers. Despite extensive knowledge of its biology, we are still unaware of the precise molecular mechanisms that sustain its oncogenic activity. Amplification of the physiologic control of DNA replication initiation by Myc upon deregulation of its expression in primary cells and transgenic mouse B-cells causes replication stress and subsequent DNA damage. Replication stress is a phenomenon often seen in early cancers from different tissue origin, and it is believed to be consequent to oncogene activation. However, formal proof for its requirement during tumorigenesis is yet to be obtained. The long-term goal of this project is to characterize the contribution of Myc-dependent replication stress to B-cell lymphomagenesis. We will specifically assess whether altering Myc's ability to promote replication stress - by either ablating its ability to control DNA replication or modifying the cellular responses to Myc- dependent replication stress- determines the outcome of the oncogenic process. We hypothesize that pathways coping with replication stress restrain tumor initiation driven by this protooncogene and hence, manipulation of these pathways will determine Myc's ability to generate lymphomas when deregulated in B-cells.
This Research Plan is meant to be part of a Career Development Plan through which I aim to obtain critical knowledge and technical skills on: (1) the application of mouse models to the study cancer initiation and progression; and (2) the use of high- throughput technologies and Systems Biology to address general questions in the cancer field that, due to their complexity, require integrated approaches. The extraordinary characteristics of the host center, where all these disciplines are integrated for the study of cancer, ensure an optimal environment for the training period. The mentored phase will therefore allow me to transit with success to an independent phase, where to continue to develop the final parts of this research project, obtain proof of principle for the above proposed research hypothesis, and pursue the study of the basic mechanisms of Myc-dependent B-cell lymphomagenesis, with aim to find novel therapeutic targets for this group of diseases.
PUBLIC HEALTH RELEVANCE: Loss of normal control of Myc protein activity occurs in more than 70% of human cancers, and is essential for their initiation, growth and progression. This project proposes to examine the requirement during tumor development of a novel mechanism used by Myc to control cellular proliferation. Confirmation of this requirement will point to this function as a potential novel therapeutic target in a majority of cancer types.
描述(由申请人提供):c-Myc 原癌基因的表达失调是许多人类癌症发生的常见必要条件。尽管对其生物学有广泛的了解,但我们仍然不知道维持其致癌活性的精确分子机制。原代细胞和转基因小鼠 B 细胞中 Myc 表达失调后,Myc 对 DNA 复制起始的生理控制放大,导致复制应激和随后的 DNA 损伤。复制应激是不同组织来源的早期癌症中常见的现象,并且被认为是癌基因激活的结果。然而,尚未获得肿瘤发生过程中其需要的正式证据。该项目的长期目标是确定 Myc 依赖性复制应激对 B 细胞淋巴瘤发生的影响。我们将具体评估改变Myc促进复制应激的能力——通过消除其控制DNA复制的能力或改变细胞对Myc依赖性复制应激的反应——是否决定致癌过程的结果。我们假设应对复制应激的途径抑制了由该原癌基因驱动的肿瘤发生,因此,对这些途径的操纵将决定 Myc 在 B 细胞中失调时产生淋巴瘤的能力。
该研究计划旨在成为职业发展计划的一部分,通过该计划我的目标是获得以下方面的关键知识和技术技能:(1)应用小鼠模型来研究癌症的发生和进展; (2) 使用高通量技术和系统生物学来解决癌症领域的一般问题,由于其复杂性,需要综合方法。主办中心的非凡特点将所有这些学科整合在一起进行癌症研究,确保了培训期间的最佳环境。因此,指导阶段将使我能够成功过渡到独立阶段,继续开发该研究项目的最后部分,获得上述提出的研究假设的原理证明,并继续研究 Myc 的基本机制依赖性B细胞淋巴瘤发生,旨在为此类疾病寻找新的治疗靶点。
公共健康相关性:超过 70% 的人类癌症都会失去对 Myc 蛋白活性的正常控制,这对于癌症的发生、生长和进展至关重要。该项目旨在研究肿瘤发展过程中 Myc 用于控制细胞增殖的新机制的需求。这一要求的确认将表明该功能作为大多数癌症类型的潜在新型治疗靶点。
项目成果
期刊论文数量(1)
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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David Dominguez-Sola其他文献
David Dominguez-Sola的其他文献
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{{ truncateString('David Dominguez-Sola', 18)}}的其他基金
Decay Accelerating Factor and B cell Immunity
衰变加速因子和 B 细胞免疫
- 批准号:
10406250 - 财政年份:2019
- 资助金额:
$ 14.46万 - 项目类别:
Decay Accelerating Factor and B cell Immunity
衰变加速因子和 B 细胞免疫
- 批准号:
10623288 - 财政年份:2019
- 资助金额:
$ 14.46万 - 项目类别:
Role of FOXO1 mutations in the pathogenesis of B cell non-Hodgkin lymphomas
FOXO1突变在B细胞非霍奇金淋巴瘤发病机制中的作用
- 批准号:
10334435 - 财政年份:2018
- 资助金额:
$ 14.46万 - 项目类别:
Role of FOXO1 mutations in the pathogenesis of B cell non-Hodgkin lymphomas
FOXO1突变在B细胞非霍奇金淋巴瘤发病机制中的作用
- 批准号:
10087895 - 财政年份:2018
- 资助金额:
$ 14.46万 - 项目类别:
ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS
复制应激在 MYC 依赖性淋巴细胞生成过程中的作用
- 批准号:
7962386 - 财政年份:2010
- 资助金额:
$ 14.46万 - 项目类别:
Role of Replication Stress during Myc-dependent Lymphomagenesis
复制应激在 Myc 依赖性淋巴瘤发生过程中的作用
- 批准号:
8785173 - 财政年份:2010
- 资助金额:
$ 14.46万 - 项目类别:
Role of Replication Stress during Myc-dependent Lymphomagenesis
复制应激在 Myc 依赖性淋巴瘤发生过程中的作用
- 批准号:
8819518 - 财政年份:2010
- 资助金额:
$ 14.46万 - 项目类别:
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