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
• 负责人: David Dominguez-Sola
• 金额: $ 24.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819518
• 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; 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; response; screening; skills; success; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT (30 LINES) 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.

项目概要/摘要（30 行） c-Myc 原癌基因的表达失调是 许多人类癌症的发展。尽管我们对其生物学有广泛的了解，但我们仍然 仍然不知道维持其致癌活性的精确分子机制。 Myc 对 DNA 复制起始的生理控制的放大 原代细胞和转基因小鼠 B 细胞中其表达失调会导致 复制压力和随后的 DNA 损伤。复制压力是一种现象 常见于来自不同组织来源的早期癌症，并且被认为是 癌基因激活的结果。然而，其要求的正式证明 肿瘤发生机制尚未明确。该项目的长期目标是表征 Myc 依赖性复制应激对 B 细胞淋巴瘤发生的贡献。我们将 特别评估是否改变 Myc 促进复制压力的能力 - 通过 消除其控制 DNA 复制的能力或改变细胞对 Myc- 的反应 依赖性复制压力-决定致癌过程的结果。我们 假设应对复制应激的途径抑制肿瘤的发生 通过这个原癌基因，因此，操纵这些途径将决定 Myc 当 B 细胞失调时产生淋巴瘤的能力。 该研究计划是职业发展计划的一部分，通过该计划我 旨在获得以下方面的关键知识和技术技能：（1）鼠标的应用 研究癌症发生和进展的模型；和（2）使用高 通量技术和系统生物学解决癌症中的一般问题 由于其复杂性，需要综合方法的领域。非凡的 主办中心的特点，所有这些学科都整合在一起进行研究 癌症，确保训练期间的最佳环境。指导阶段 因此，我将能够成功地过渡到一个独立的阶段，在那里 继续开发该研究项目的最后部分，获得原理证明 上述提出的研究假设，并对其基本机制进行研究 Myc 依赖性 B 细胞淋巴瘤发生的研究，旨在寻找新的治疗靶点 对于这组疾病。