Role of Replication Stress during Myc-dependent Lymphomagenesis

项目摘要/摘要(30行) C-Myc原癌基因的非调控表达是乳腺癌的常见必要条件 许多人类癌症的发展。尽管我们对它的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确切分子机制。 Myc对DNA复制启动的生理调控作用的放大 其在原代细胞和转基因小鼠B细胞中表达的解除调控导致 复制压力和随之而来的DNA损伤。复制应激是一种现象 常见于来自不同组织来源的早期癌症，据信 是癌基因激活的结果。然而，其要求的正式证明在 肿瘤的发生还有待于研究。这个项目的长期目标是 依赖Myc的复制应激在B细胞淋巴瘤发生中的作用我们会 具体评估是否通过以下方式改变Myc促进复制压力的能力 削弱其控制DNA复制或改变细胞对Myc-1的反应的能力 依赖复制应激--决定致癌过程的结果。我们 假设应对复制应激的通路抑制肿瘤启动驱动 因此，对这些通路的操纵将决定Myc的 当B细胞被解除调控时，发生淋巴瘤的能力。 本研究计划是职业发展计划的一部分，通过该计划，我 目的获取以下关键知识和技能：(1)鼠标的应用 用于研究癌症发生和发展的模型；以及(2)使用高密度脂蛋白。 吞吐量技术和系统生物学以解决癌症中的一般问题 这一领域由于其复杂性，需要采取综合办法。不平凡的 主办中心的特点，在那里所有这些学科都被整合起来进行研究 为了预防癌症，确保培训期间有一个最佳的环境。指导阶段 因此将使我能够成功地过渡到一个独立的阶段，在那里 继续开发本研究项目的最后部分，获得原则证明 提出了上述研究假设，并对其基本机制进行了深入研究 Myc依赖的B细胞淋巴瘤的研究，旨在寻找新的治疗靶点 治疗这类疾病。

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.