Genome Stability Regulation by the Nuclear Pore-Chromosome Axis and Defects in Tumor Cells

核孔染色体轴的基因组稳定性调节和肿瘤细胞的缺陷

• 批准号: 9162317
• 负责人: Veronica Rodriguez-Bravo
• 金额: $ 18.36万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9162317
• 关键词: Affect; Anaphase; Aneuploidy; Area; Binding; Biology; Cancer Cell Growth; Cell Proliferation; Cell Survival; Cell division; Cells; Chromosomal Gain; Chromosomal Instability; Chromosomal Loss; Chromosomal Stability; Chromosome abnormality; Chromosomes; Complex; Data; Dedications; Defect; Docking; Dreams; Ensure; Environment; Faculty; Failure; Frequencies; Funding; Future; Genome; Genome Stability; Goals; Grant; Human; Interphase; K-Series Research Career Programs; Kinetochores; Learning; Learning Skill; Link; Maintenance; Malignant Neoplasms; Manuscripts; Mentors; Mentorship; Methodology; Methods; Microtubules; Mission; Mitosis; Mitotic; Mitotic Checkpoint; Mitotic Chromosome; Mitotic spindle; Molecular; Mutation; Nuclear; Nuclear Pore; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Oncogenic; Pathogenesis; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Production; Proteins; Regulation; Research; Research Personnel; Resolution; Role; Scheme; Scientist; Secure; Signal Transduction; Site; System; Technical Expertise; Therapeutic; Time; United States National Institutes of Health; Veronica; Work; Writing; anticancer research; base; cancer cell; career; cell growth; feeding; frontier; genome integrity; inhibitor/antagonist; insight; neoplastic cell; novel; prevent; skills; targeted treatment; tumor; tumorigenic

Project Summary The applicant, Veronica Rodriguez-Bravo, is committed to a long-lasting career in cancer research. Her goal is to become an independent investigator to study genome stability maintenance mechanisms regulated by nuclear pores (NPCs) and the mitotic checkpoint and the impact of defects on cancer. Veronica's three-year proposal will allow her to acquire skills to rigorously study NPC regulation in non- tumor and tumor cells and professional abilities necessary to become a successful independent group leader in the current challenging funding environment for young investigators. The scientific proposal aims to study the molecular and cellular details of the NPC-mitotic checkpoint axis that controls chromosomal stability and how errors impact tumor and non-tumor cells. Specifically, the proposed Aims seek to obtain mechanistic insights into how human cells integrate signals from the nuclear periphery (NPCs) and from mitotic chromosomes to protect genome integrity and examine how failure of these pathways contribute to chromosomal and NPC defects found in human cancers. Aim 1 will study the redundant regulation of Mad1, a key mitotic checkpoint protein, recruitment to chromosomes in mitosis and consequences of defects for tumor and non-tumor cells. Aim 2 will analyze the inter-connection and regulation of the NPC components implicated in the pre-mitotic signaling necessary for high fidelity mitosis. Aim 3 will examine how errors affecting the mitotic and the NPC signaling impact chromosomal stability, tumor cell division and survival and how weaknesses in tumor cells can be exploited for potential future targeted therapies. This proposal will generate essential data to understand how chromosomal and NPC signals feed to each other to ensure protection against chromosomal errors commonly found in cancer and also provide insights into how NPC defects and chromosomal abnormalities benefit tumor cell growth, survival and proliferation. With the mentorship of Dr. Jallepalli, and co-mentor Dr. Foley, the candidate will be able to expand her research skills, learn to write successful R01-type grants, produce preliminary new data for one or two manuscripts as corresponding author, secure a faculty position and interact with other scientists and collaborators to set the ground for a successful independent career. Importantly, she will acquire new technical skills learning novel methodologies of NPC sub-complexes purification from human cells to interrogate NPC composition and posttranslational modifications in tumor and non-tumor cells. In summary, Veronica and her mentors believe this proposal will be a critical opportunity to set the basis of her independent career as a biomedical cancer researcher and thus fulfill her dream of dedication to the study of cancer. In conclusion, this K award will be fundamental to provide Veronica protected time to successfully transition to research independence and contribute to the mission of the NIH and NCI.

项目摘要 申请人Veronica Rodriguez-Bravo致力于从事癌症研究的持久职业。她 目标是成为研究基因组稳定性维持机制的独立研究者 受核孔（NPC）和有丝分裂检查点以及缺陷对癌症的影响。 维罗妮卡（Veronica）的三年提案将使她能够获得技能，可以严格研究非律师的规定 肿瘤和肿瘤细胞以及成为成功独立组所需的专业能力 在当前为年轻调查人员提供挑战的资金环境中的领导者。 科学建议旨在研究NPC麦图质检查点轴的分子和细胞细节 控制染色体稳定性以及误差如何影响肿瘤和非肿瘤细胞。具体来说， 拟议的目的旨在获取机械洞察人类细胞如何整合来自的信号 核外围（NPC）和从有丝分裂染色体来保护基因组完整性并检查如何 这些途径的失败导致人类癌症中发现的染色体和NPC缺陷。目标1 将研究MAD1的冗余调节，这是一种关键有丝分裂检查点蛋白，募集到 有丝分裂的染色体和肿瘤和非肿瘤细胞缺陷的后果。 AIM 2将分析 NPC组件的连接间和调节与有丝分裂前信号传导有关 高保真有丝分裂所必需的。 AIM 3将检查如何影响有丝分裂和NPC的错误 信号传导会影响染色体稳定性，肿瘤细胞分裂和存活以及肿瘤中的弱点 可以利用细胞来实现未来的靶向疗法。该建议将生成基本数据 了解染色体和NPC信号如何相互馈送，以确保防止 在癌症中常见的染色体错误，还提供了有关NPC缺陷和如何的见解 染色体异常有益于肿瘤细胞的生长，生存和增殖。 在Jallepalli博士的指导下以及Foley博士的指导下，候选人将能够扩大她 研究技能，学习撰写成功的R01型赠款，生成一两个初步的新数据 作为对应作者的手稿，确保教师职位并与其他科学家互动， 合作者为成功的独立职业奠定了基础。重要的是，她将获得新的 技术技能学习NPC子复合物从人类细胞纯化到 在肿瘤和非肿瘤细胞中询问NPC组成和翻译后修饰。 总而言之，维罗妮卡和她的导师认为，该提议将是设定基础的关键机会 她作为生物医学癌症研究员的独立职业，因此实现了她奉献的梦想 癌症研究。总之，该K奖将是为了提供维罗妮卡保护的时间至关重要 成功地过渡到研究独立性，并为NIH和NCI的使命做出贡献。