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: 9330819
• 负责人: Veronica Rodriguez-Bravo
• 金额: $ 5.98万
• 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 2017-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330819
• 关键词: Affect; Anaphase; Aneuploidy; Antimitotic Agents; Area; Biology; Cancer Cell Growth; Cell Proliferation; Cell Survival; Cell division; Cells; Chromosomal Gain; 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; MXD1 gene; 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 Proteins; Oncogenic; Pathogenesis; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Production; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Resolution; Role; Scheme; Scientist; Secure; Signal Transduction; Site; System; Technical Expertise; Therapeutic; Time; Tumorigenicity; United States National Institutes of Health; Veronica; Work; Writing; anticancer research; cancer cell; cancer survival; 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致力于长期从事癌症研究。她 我的目标是成为一名独立的研究人员，研究基因组稳定性维持机制 受核孔（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技能，严格学习非国家的NPC监管， 成为一个成功的独立团体所必需的肿瘤和肿瘤细胞及专业能力 在目前充满挑战的资金环境中，年轻的研究人员。 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。具体而言是 提出的目的是寻求获得人类细胞如何整合来自 核周边（NPC）和有丝分裂染色体，以保护基因组的完整性，并研究如何 这些途径的失败导致了在人类癌症中发现的染色体和NPC缺陷。要求1 将研究Mad 1的冗余调节，Mad 1是一种关键的有丝分裂检查点蛋白， 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组分的相互连接和调节 是高保真有丝分裂所必需的。目标3将研究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如何 细胞可用于潜在的未来靶向治疗。该提案将产生必要的数据， 了解染色体和NPC信号如何相互馈送，以确保保护免受 癌症中常见的染色体错误，也提供了关于NPC缺陷和 染色体异常有利于肿瘤细胞生长、存活和增殖。 在贾勒帕利博士和福利博士的指导下，候选人将能够扩大她的 研究技能，学会写成功的R 01型赠款，产生初步的新数据，为一个或两个 手稿作为通讯作者，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 学习从人类细胞中纯化NPC亚复合物的新方法， 研究肿瘤和非肿瘤细胞中NPC组成和翻译后修饰。 总而言之，维诺尼卡和她的导师们相信这个提议将是一个关键的机会， 她作为一个生物医学癌症研究人员的独立职业生涯，从而实现她的梦想，致力于 对癌症的研究总之，这个K奖将是为维罗妮卡提供保护时间的基础， 成功地过渡到研究独立，并为NIH和NCI的使命做出贡献。