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: 8146177
• 负责人: David Dominguez-Sola
• 金额: $ 14.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8146177
• 关键词: Address; Adoptive Transfer; Affect; B-Cell Lymphomas; B-Lymphocytes; Biological; Biological Assay; Biology; Cell Proliferation; Cells; Characteristics; Complementary DNA; DNA Damage; DNA biosynthesis; Development; Development Plans; Discipline; Disease; Engineering; Ensure; Environment; Epigenetic Process; Event; Gene Library; Genes; Genetic; Genetic Transcription; Goals; Growth; Hematopoietic stem cells; Human; In Vitro; Knowledge; Lesion; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Measures; Mentors; Molecular; Mus; Mutagenesis; Oncogene Activation; Oncogenes; Oncogenic; Open Reading Frames; Outcome; Pathway interactions; Phase; Phenotype; Physiological; Process; Proteins; Proto-Oncogenes; Relative (related person); Replication Initiation; Reporter; Research; Research Project Grants; Role; Screening procedure; Stress; System; Systems Biology; Techniques; Testing; Tissues; Training; Transcriptional Regulation; Transgenic Mice; Validation; Variant; abstracting; base; c-myc Genes; cancer initiation; cancer therapy; cancer type; career development; cell transformation; coping; high throughput technology; in vivo; insight; interest; mouse model; mutant; neoplastic cell; new therapeutic target; novel; overexpression; public health relevance; response; skills; success; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

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原孕元的放松调节表达是许多人类癌症的发展经常必要的。尽管了解了其生物学，但我们仍然没有意识到维持其致癌活性的精确分子机制。 MYC在放松原代细胞表达和转基因小鼠B细胞中对DNA复制启动的生理控制的扩增会导致复制应力和随后的DNA损伤。复制应激是从不同组织起源的早期癌症中经常出现的一种现象，据信这是癌基因激活的结果。但是，尚未获得正式证明其在肿瘤发生过程中的要求。该项目的长期目标是表征MYC依赖性复制应力对B细胞淋巴细胞化的贡献。我们将特别评估MYC促进复制应力的能力是否通过消融其控制DNA复制的能力或修改对MYC依赖性复制应力的细胞反应的能力来确定致癌过程的结果。我们假设应对复制应力的途径限制了由这种原子能元素驱动的肿瘤起始，因此，对这些途径的操纵将决定MYC在B细胞中放松管制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，我旨在获得以下方面的关键知识和技术技能：（1）将鼠标模型应用于研究癌症的启动和进展； （2）使用高通量技术和系统生物学来解决癌症领域中的一般问题，这些问题由于其复杂性需要集成的方法。所有这些学科都集成为癌症的宿主中心的非凡特征，确保了培训期的最佳环境。因此，这一指导阶段将使我能够成功地传输到一个独立的阶段，在该阶段继续开发该研究项目的最终部分，获得上述研究假设的原理证明，并追求对MYC依赖性B细胞淋巴作用的基本机制的研究，旨在找到这组疾病的新型治疗靶标。 公共卫生相关性：超过70％的人类癌症发生了对MYC蛋白活性的正常控制的丧失，对于它们的启动，生长和进展至关重要。该项目建议检查MYC用于控制细胞增殖的新机制的肿瘤发展过程中的需求。确认这一要求将向大多数癌症类型中的潜在新型治疗靶标表示该功能。