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.

项目概要 申请人维罗妮卡·罗德里格斯·布拉沃 (Veronica Rodriguez-Bravo) 致力于癌症研究领域的长期职业生涯。她 目标是成为研究基因组稳定性维持机制的独立研究者 核孔（NPC）和有丝分裂检查点的调节以及缺陷对癌症的影响。 维罗妮卡的三年提案将使她获得严格研究非人大监管的技能。 肿瘤和肿瘤细胞以及成为一个成功的独立团体所必需的专业能力 在当前年轻研究者面临的充满挑战的资助环境中处于领先地位。 该科学提案旨在研究 NPC 有丝分裂检查点轴的分子和细胞细节 控制染色体稳定性以及错误如何影响肿瘤和非肿瘤细胞。具体来说， 拟议的目标旨在获得关于人类细胞如何整合来自细胞的信号的机制见解。 核外围 (NPC) 和有丝分裂染色体，以保护基因组完整性并检查如何 这些途径的失败会导致人类癌症中发现的染色体和 NPC 缺陷。目标1 将研究 Mad1（一种关键的有丝分裂检查点蛋白）的冗余调节，招募 有丝分裂中的染色体以及肿瘤和非肿瘤细胞缺陷的后果。目标2将分析 有丝分裂前信号传导中涉及的 NPC 成分的相互连接和调节 高保真有丝分裂所必需的。目标 3 将检查错误如何影响有丝分裂和 NPC 信号传导影响染色体稳定性、肿瘤细胞分裂和存活以及肿瘤的弱点 细胞可用于未来潜在的靶向治疗。该提案将生成必要的数据 了解染色体和 NPC 信号如何相互传递，以确保免受侵害 癌症中常见的染色体错误，也提供了有关 NPC 缺陷和如何发生的见解 染色体异常有利于肿瘤细胞的生长、存活和增殖。 在 Jallepalli 博士和共同导师 Foley 博士的指导下，候选人将能够扩展她的能力 研究技能，学习撰写成功的 R01 型补助金，为一两个项目生成初步新数据 作为通讯作者的手稿，获得教职并与其他科学家互动， 合作者为成功的独立职业生涯奠定基础。重要的是，她将获得新的 技术技能学习从人体细胞中纯化 NPC 亚复合物的新方法 研究肿瘤和非肿瘤细胞中的 NPC 组成和翻译后修饰。 总之，维罗妮卡和她的导师相信这个提案将是一个奠定基础的关键机会 她作为一名生物医学癌症研究员的独立职业生涯，从而实现了她奉献于癌症领域的梦想 癌症研究。总之，这个 K 奖对于为维罗妮卡提供受保护的时间至关重要 成功过渡到研究独立，并为 NIH 和 NCI 的使命做出贡献。