Dynamics of cellular senescence in single human cells

单个人类细胞的细胞衰老动力学

• 批准号: 8732676
• 负责人: Jeremy Purvis
• 金额: $ 34.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732676
• 关键词: Address; Affect; Apoptosis; Award; Biological Assay; Biological Process; Biology; Breast Epithelial Cells; CDKN1A gene; CDKN2A gene; Cell Aging; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Characteristics; Commit; Complex; DNA Damage; Data; Doctor of Philosophy; Dose; End Point Assay; Event; Exhibits; Fibroblasts; Foundations; Genes; Genotoxic Stress; Goals; Human; Hypoxia; Image; Individual; Life; MAPK14 gene; Machine Learning; Mediating; Mentors; Microscopy; Modeling; Molecular Profiling; Monitor; Mus; Oncogene Activation; Pathway interactions; Phase; Phase Transition; Phenotype; Population; Prevention; Procedures; Process; Protein p53; Regulatory Element; Reporter; Research; Resolution; Series; Signal Transduction; Stress; System; Testing; Therapeutic; Time; Training; Tumor Suppressor Genes; abstracting; base; biological adaptation to stress; cancer cell; career; cell fixing; cell type; cellular imaging; chromatin immunoprecipitation; genome-wide; human disease; in vivo; knock-down; medical schools; novel; premature; prevent; programs; response; senescence; therapeutic target; time use; tool; tumor; tumor progression

Project Summary/Abstract Dynamics of cellular senescence in single human cells The goal of this proposal is to investigate the timing and control of cellular senescence in single human cells. Senescence is a state of permanent cell cycle arrest and an inherent defense against tumor progression. Exploiting senescence for therapeutic gain will require a better understanding of basic senescence biology, novel experimental tools to study the phenotype at single-cell resolution, and computational approaches to understand how cells integrate multiple senescence signals. This proposal provides a career transition plan for Dr. Jeremy Purvis that will equip him with the additional training necessary to study senescence at single-cell resolution and form the foundation for developing treatments that induce premature senescence in cells with defective stress responses. During the mentored phase of the award (K99), he will develop a live-cell imaging system for monitoring DNA damage-induced senescence in real time and use this system to determine how upstream signaling of the tumor suppressor p53 control expression of senescence markers (Aim 1). This critical phase of training will be co-supervised by Dr. Galit Lahav and Dr. Peter Sorger (Harvard Medical School), who are both experts in time-lapse microscopy and cell fate decision processes. During the transition to independence (K99/R00), he will identify transcriptional regulators that initiate expression of the key senescence regulator p16INK4a and characterize the dynamics of this transition (Aim 2). The final step in achieving independence (R00) will involve transferring these tools and concepts to study senescence in primary cells lines, focusing specifically on how multiple signals are integrated to achieve a senescence decision (Aim 3). This three-phase transition plan will illuminate our basic understanding of cellular senescence and provide an extensible computational/experimental platform for identifying therapies that induce premature senescence in cancer cells. These aims are highly congruent with the NIGMS's primary goal of supporting basic discoveries that advance the treatment and prevention of human disease.

项目摘要/摘要 单个人类细胞中细胞衰老的动力学 该建议的目的是研究单个人类细胞中细胞衰老的时间和控制。 衰老是永久性细胞周期停滞的状态，也是针对肿瘤进展的固有防御。 利用衰老以获得治疗增益将需要更好地了解基本衰老生物学， 在单细胞分辨率下研究表型的新型实验工具，以及计算方法 了解细胞如何整合多个衰老信号。该建议提供了职业过渡计划 杰里米·普维斯（Jeremy Purvis）博士将使他接受单细胞研究衰老所需的额外培训 分辨率并构成开发治疗的基础 不良压力反应。在奖项的指导阶段（K99）中，他将开发一个活细胞成像 用于监测DNA损伤引起的实时衰老的系统，并使用该系统来确定如何 肿瘤抑制器p53控制衰老标记的上游信号传导（AIM 1）。这 Galit Lahav博士和Peter Sorger博士将共同监督培训的关键阶段（哈佛医学 学校），既是延时显微镜和细胞命运决策过程的专家。在过渡期间 为了独立（K99/r00），他将确定启动钥匙表达的转录调节器 衰老调节剂p16ink4a并表征了这种过渡的动力学（AIM 2）。最后一步 实现独立性（R00）将涉及转移这些工具和概念以研究衰老 主要单元线线，专门关注多个信号如何集成以实现衰老 决定（目标3）。这个三相过渡计划将阐明我们对细胞的基本理解 衰老并提供可扩展的计算/实验平台，用于识别疗法 在癌细胞中诱导过早衰老。这些目标与裸球的主要目标非常一致 支持基本发现，以促进人类疾病的治疗和预防。