Progressive states of cell-cycle withdrawal

细胞周期退出的进行性状态

• 批准号: 10803979
• 负责人: Sabrina Leigh Spencer
• 金额: $ 34.96万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10803979
• 关键词: Age; Aging; Algorithms; Biological Markers; Biology; Cell Aging; Cell Culture Techniques; Cell Cycle; Cell Cycle Progression; Cell Separation; Cell division; Cell physiology; Cells; Chronic Disease; Chronology; DNA Damage; Development; Disease; Drug usage; Event; Flow Cytometry; Functional disorder; Genotoxic Stress; Health Care Costs; Human; Knowledge; Length; Light; Malignant Neoplasms; Measures; Medical; Microscopy; Modeling; Modernization; Molecular; Morbidity - disease rate; Nature; Pathology; Pharmaceutical Preparations; Physiological; Population; Probability; Process; Proliferating; Regenerative capacity; Rejuvenation; Relapse; Rest; Role; Safety; Somatic Cell; Sorting; Technology; Testing; Therapeutic; Withdrawal; Work; cancer therapy; cell age; cell injury; chemotherapeutic agent; genetic signature; genotoxicity; human disease; human old age (65+); improved; inflammatory milieu; molecular marker; mortality; predictive signature; prevent; reproductive; senescence; sensor; single cell technology; single-cell RNA sequencing; telomere; transcriptomics; tumor

Project Summary Senescence is the process by which a cell permanently stops proliferating due to cellular aging or damage but does not die. Induction of senescence is often desirable during cancer treatment to prevent the proliferation of aberrant cells, but it also impedes cellular function and regenerative capacity as we age. The study of cellular senescence is hindered by the fact that senescence is difficult to distinguish from other states of cell-cycle withdrawal such as quiescence, a transient cellular resting state. This is because quiescence and senescence are defined by overlapping molecular markers and because these cell-cycle transitions occur heterogeneously from cell to cell. Despite obvious medical relevance, it is unclear whether senescence and quiescence are truly distinct states. Here we propose to test the hypothesis that senescence and quiescence exist on a continuum of cell-cycle withdrawal where the probability of cell-cycle re-entry steadily declines toward zero as cells become senescent. We will leverage our unique expertise in long-term, time-lapse microscopy, automated single- cell tracking, and the development of sensors for cell-cycle progression and cell-cycle withdrawal to unveil gradations of cell-cycle withdrawal that are invisible by standard bulk approaches. Our specific aims are 1) To determine the predictive power of prevailing senescence markers as binary markers of senescence and as graded markers of quiescence depth, 2) To determine at the transcriptomic level whether quiescence and senescence are distinct states or part of a continuum of cell-cycle withdrawal, and 3) To the identify the DNA damage and telomere features that predict permanent cell-cycle withdrawal as cells age toward replicative senescence. If successful, this work will improve our ability to define molecularly the state of senescence and will generate new fundamental knowledge about the onset of senescence. Our work could improve the ability to predict tumor relapse after cancer therapy, help quantify a cell’s physiological age and reproductive potential, identify ways to rejuvenate aged cells, and improve the safety of senolytic drugs that eliminate senescent cells.

项目概要 衰老是细胞由于细胞老化而永久停止增殖的过程 或损坏但不会死亡。在癌症治疗过程中通常需要诱导衰老 防止异常细胞的增殖，但它也会阻碍细胞功能和 随着年龄的增长，再生能力。细胞衰老的研究受到以下事实的阻碍： 衰老很难与细胞周期退出的其他状态区分开来，例如 静止，短暂的细胞静止状态。这是因为静止和衰老是 由重叠的分子标记定义并且因为这些细胞周期转变发生 细胞与细胞之间存在异质性。尽管有明显的医学相关性，但尚不清楚是否 衰老和静止是真正不同的状态。在这里我们建议检验假设 衰老和静止存在于细胞周期退出的连续过程中，其中 随着细胞衰老，细胞周期重新进入的概率稳步下降至零。 我们将利用我们在长期、延时显微镜、自动单 细胞追踪以及细胞周期进展和细胞周期传感器的开发 撤退以揭示细胞周期撤退的分级，这是标准体积看不见的 接近。我们的具体目标是 1) 确定流行趋势的预测能力 衰老标记作为衰老的二元标记和静止的分级标记 深度，2）在转录组水平上确定静止和衰老是否是 细胞周期退出的不同状态或连续体的一部分，以及 3) 识别 DNA 损伤和端粒特征可预测随着细胞老化而出现永久性细胞周期退出 复制性衰老。 如果成功，这项工作将提高我们从分子角度定义衰老状态的能力 将产生有关衰老开始的新基础知识。我们的工作可以 提高预测癌症治疗后肿瘤复发的能力，帮助量化细胞的 生理年龄和生殖潜力，找出使衰老细胞恢复活力的方法，以及 提高消除衰老细胞的衰老药物的安全性。