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

项目摘要 申请者Veronica Rodriguez-Bravo致力于癌症研究的长期职业生涯。她 目标是成为研究基因组稳定性维持机制的独立调查者 受核孔(NPC)和有丝分裂检查点以及缺陷对癌症的影响的调节。 维罗妮卡的三年计划将使她获得技能，严格研究非 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 在当前具有挑战性的资金环境中，年轻调查人员处于领先地位。 这项科学提案旨在研究NPC-有丝分裂检查点轴的分子和细胞细节。 它控制着染色体的稳定性，以及错误如何影响肿瘤和非肿瘤细胞。具体地说， 提出的目标是寻求获得对人类细胞如何整合来自 核周(Npc)和有丝分裂染色体，以保护基因组的完整性，并研究如何 这些通路的失败导致了人类癌症中发现的染色体和鼻咽癌缺陷。目标1 将研究MAD1的冗余调节，MAD1是一种关键的有丝分裂检查点蛋白，招募到 有丝分裂中的染色体及缺陷对肿瘤和非肿瘤细胞的影响。AIM 2将分析 有丝分裂前信号转导中鼻咽癌成分的相互联系和调控 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鼻咽癌 信号影响染色体稳定性、肿瘤细胞分裂和存活以及肿瘤中的弱点 细胞可以被开发为未来潜在的靶向治疗。该提案将生成关键数据，以 了解染色体和鼻咽癌信号如何相互传递以确保对 染色体错误在癌症中常见，也为了解鼻咽癌缺陷和 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Foley博士的共同指导下，候选人将能够扩展她的能力 研究技能，学习撰写成功的R01型赠款，为一两个项目提供初步的新数据 手稿作为通讯作者，确保教师职位，并与其他科学家和 合作者为成功的独立事业奠定了基础。重要的是，她将获得新的 从人细胞中学习鼻咽癌亚复合体纯化新方法的技术技能 询问肿瘤和非肿瘤细胞中鼻咽癌的组成和翻译后修饰。 总而言之，维罗妮卡和她的导师们相信，这项提议将是奠定基础的关键机会 作为一名生物医学癌症研究人员的独立职业生涯，从而实现了她致力于 对癌症的研究。总而言之，这一K奖将是为Veronica提供受保护的时间的根本 成功过渡到研究独立，并为NIH和NCI的使命做出贡献。

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.