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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.

项目总结