Nuclear body assembly and function in telomerase-free cancer cells

无端粒酶癌细胞中的核体组装和功能

• 批准号: 9910375
• 负责人: Huaiying Zhang
• 金额: $ 16.61万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-08 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910375
• 关键词: Acute Promyelocytic Leukemia; Area; Behavior; Biochemistry; Biological; Biology; Body Composition; Cancer Biology; Cancer Cell Growth; Cells; Characteristics; Chemicals; Cytoplasmic Granules; DNA Damage; DNA Repair; Data; Dependence; Diagnosis; Diffuse; Dimerization; Discipline; Doctor of Philosophy; Exhibits; Future; Goals; In Vitro; Knowledge; Laboratories; Length; Ligase; Lipid Bilayers; Liquid substance; Malignant Neoplasms; Mediation; Membrane; Modeling; Molecular; Monitor; Nature; Nuclear; Oncology; Organelles; Phase; Phase Transition; Phenotype; Physical condensation; Physics; Positioning Attribute; Process; Property; Protein Engineering; Proteins; RNA; Research; Research Personnel; Role; Shapes; Signal Transduction; Structure; Subcellular structure; Technical Expertise; Telomerase; Telomere Maintenance; Telomere Pathway; Telomere Shortening; Telomere-Binding Proteins; Testing; Time; Training; Ubiquitin; Work; anticancer research; base; cancer cell; cancer therapy; career; homologous recombination; innovation; interdisciplinary approach; interest; molecular dynamics; multidisciplinary; optogenetics; physical science; predictive modeling; professor; recruit; repaired; response; self assembly; skills; stress granule; targeted cancer therapy; telomere; tool

My overall career goal is to become an established cancer cell biologist who employs multidisciplinary approaches to determine how phase transition is used to promote cancer cell growth and to develop strategies targeting these processes for cancer therapy. My interest in self-assembly of biological matter originated from my Ph.D. work on molecular dynamics in lipid bilayers and postdoctoral work on phase separation of RNA granules. Supported by the Physical Science Oncology Center (PSOC) at Penn, I started working in cancer in my current postdoctoral position at Penn since 2015 and became interested in cell and molecular physics of cancer. I decided to focus my independent research in this area and initiated a project that I will bring with me to my future laboratory. My project concerns telomerase-negative cancer cells that rely on an alternative lengthening of telomeres (ALT) pathway to maintain telomere length. The presence of ALT- associated promyelocytic leukemia nuclear bodies (APBs) is a unique characteristic of ALT and is used for diagnosis. APBs are essential for telomere maintenance in ALT, but both how they form and how they function in telomere lengthening, which is a crucial part of the ALT cancer phenotype, are unknown. I observed that APBs induced by DNA damage at telomeres exhibit behavior characteristic of liquid phase condensation, leading me to hypothesize that telomere shortening in ALT cells induces nucleation of APB condensates as a mechanism for telomere elongation. The liquid nature of APBs would promote coalescence of APBs to cluster telomeres within APBs, another characteristic of ALT cells. Meanwhile, condensation of APB droplets can concentrate DNA repair factors, providing opportunities for telomeres to use one another as repair templates to elongate within APBs. I developed an optogenetic approach and induced de novo assembly of APBs that exhibit liquid behavior and coalesce to drive telomere clustering. In this K22, I will test my hypothesis for APB function to provide a basis for cancer therapy targeting APBs. Aim 1 focuses on the dependence of APB function on their material properties by asking how APB formation drives telomere clustering, and Aim 2 focuses on the dependence of APB function on their chemical composition by testing whether APB formation is sufficient for telomere synthesis. I am negotiating my offers for the position of Assistant Professor and plan to start my independent career earlier next year. With my multidisciplinary training background and exciting preliminary data that supports my hypothesis, I am well positioned to achieve my career objectives as an independent cancer researcher. However, to make the transition into cancer research smooth and successful, further training to gain knowledge and technical expertise in cancer biology, particularly on DNA repair and telomere biology, is much needed. Therefore, additional protected time from this K22 is crucial for me to focus on research, immerse in cancer biology, and develop skills bridging expertise from multiple disciplines to establish myself as an expert on liquid phase condensation in cancer.

我的整体职业目标是成为一名既有多学科的癌症细胞生物学家 确定如何使用相转换来促进癌细胞生长并发展的方法 针对这些过程进行癌症治疗的策略。我对生物学自我组装的兴趣 起源于我的博士在脂质双层中的分子动力学和阶段的博士后工作的工作 RNA颗粒的分离。在Penn的物理科学肿瘤学中心（PSOC）的支持下，我开始 自2015年以来，我目前在宾夕法尼亚州的博士后职位从事癌症工作，并对细胞感兴趣 癌症的分子物理学。我决定将我的独立研究集中在这方面，并启动了一个项目 我将带我带到未来的实验室。我的项目涉及依赖的端粒酶阴性癌细胞 端粒（ALT）途径的替代延长以保持端粒长度。 alt-的存在 相关的临时细胞白血病核体（APB）是ALT的独特特征，用于 诊断。 APB对于ALT中的端粒维护至关重要，但它们的形成方式和运作方式都是必不可少的 在端粒延长中，这是ALT癌表型的关键部分，这是未知的。我观察到了 由DNA损伤在端粒诱导的APB表现出液相冷凝的行为特征， 导致我假设Alt细胞中的端粒缩短会诱导APB的成核 凝结为端粒伸长的机制。 APB的液体性质会促进 APB的聚合以将端粒聚集在APB中，APB是ALT细胞的另一个特征。同时， APB液滴的凝结可以集中DNA修复因子，为端粒提供了机会 彼此作为修复模板在APB中伸长的模板。我开发了一种光遗传学方法并诱发了DE NOVO组装APB，表现出液体行为和合并以驱动端粒聚类。在这个K22中，我会 测试我对APB功能的假设，以提供针对APB的癌症治疗的基础。 AIM 1专注于 通过询问APB形成如何驱动端粒，APB功能对其材料属性的依赖性 聚类和AIM 2通过测试侧重于APB功能对其化学组成的依赖性 APB的形成是否足以用于端粒合成。我正在谈判我的提议 助理教授，并计划明年早些时候开始我的独立职业。接受我的多学科培训 背景和令人兴奋的初步数据支持我的假设，我有好处 作为独立癌症研究员的职业目标。但是，要过渡到癌症研究 顺利而成功，进一步培训，以获得癌症生物学方面的知识和技术专长， 特别需要在DNA修复和端粒生物学上。因此，从此额外保护的时间 K22对我来说至关重要 从多个学科确定自己是癌症液相冷凝专家。