Progressive states of cell-cycle withdrawal

细胞周期退出的进行性状态

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要衰老是由于细胞衰老而永久停止增殖的过程或损坏但不会死亡。癌症治疗期间通常需要诱导感应为了防止异常细胞的扩散，但也阻碍了细胞功能和随着年龄的增长，再生能力。细胞感应的研究受到了以下事实的阻碍感应很难与其他细胞周期戒断状态区分开，例如静止，瞬态细胞静止状态。这是因为静态和感受是由重叠的分子标记定义，并且因为这些细胞周期过渡发生从细胞到细胞异质。尽管有明显的医学相关性，但尚不清楚是否存在感应和静止是真正不同的状态。在这里，我们建议检验假设这种敏感和静止存在于细胞周期戒断的连续元素上随着细胞的感觉，细胞周期重新进入的概率稳步下降向零。我们将利用我们在长期，延时显微镜下的独特专业知识，自动化的单个细胞跟踪，以及用于细胞周期进展和细胞周期的传感器的发展提取到标准散装看不见的细胞周期提取的级别方法。我们的具体目标是1）确定流行的预测能力感应标记作为感应的二元标记和静态标记深度，2）在转录组水平上确定静止和感应是否为细胞周期戒断连续的不同状态或一部分，3）识别DNA 随着细胞的衰老而预测永久性细胞周期戒断的损伤和端粒特征复制感应。如果成功，这项工作将提高我们定义分子感应状态的能力和将产生有关感应发作的新基本知识。我们的工作可以提高癌症治疗后预测肿瘤缓解的能力，有助于量化细胞实物时代和生殖潜力，确定恢复老化细胞的方法，以及改善消除感觉细胞的鼻溶剂的安全性。