# Dynamics of Cellular Senescence in Single Cells

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $411,266

## Abstract

PROJECT SUMMARY
Cellular senescence is a stress response that stably blocks proliferation. In-vivo studies have shown that
senescing cells are present in benign or premalignant lesions and are progressively lost as the lesions become
malignant. Senescence therefore is as a major physiological barrier of tumor development, making induction of
senescence an attractive approach for cancer therapy. Current markers of senescence (e.g. SA--gal) identify
senescing cells at one static time-point and usually several days after senescence has been established. Such
assays do not allow quantification of the history of growth and dynamics of the response prior to the
establishment of senescence. My lab’s previous studies on the tumor suppressor protein p53 revealed the
importance of looking at the dynamics of signaling pathways at high temporal resolution and in single cells.
Here we propose to combine live single cells imaging approaches with bioinformatics & mathematical models
to study the temporal behavior of senescence-associated genes in individual cells in culture cells and in vivo in
response to DNA damage and oncogene activation and to determine how the dynamics of senescence
regulators is controlled and affect the decision whether a cell will senesce or arrest transiently.
In our first aim we will use live cell imaging to follow the growth and divisions of individual cells in response to
DNA damage and oncogenes for multiple days, and will connect growth trajectories with the establishment of
senescence. We will then develop live-cell reporters for cell cycle phase, DNA breaks and oncogene
expression levels to determine their effect on a cell’s probability to senesce. In Aim2 we will quantify the
dynamical behavior of senescence-associate genes in individual cultured cells and validate their regulation in-
vivo, with the goal of identifying unique temporal patterns of the factors determining whether arrest is transient
or permanent. We will also use bioinformatics tools to search for putative new senescence-associate genes
and will develop similar live cell reporters for following their dynamics in single cells following DNA damage and
oncogenic activation. Lastly, in Aim3 we will investigate the molecular mechanisms connecting internal cellular
states (e.g. cell cycle phase, number of DNA breaks, levels of oncogenes) with the unique dynamics of
senescence regulators and we will use genetic, chemical and synthetic perturbations to manipulate these
dynamics and control the entry and establishment of senescence as well as the escape from arrest.
The knowledge gained by our work will be fundamental for understanding the key circuits controlling growth,
transient arrest and senescence, and how they change dynamically in individual cells. In addition,
understanding the mechanisms that control senescence and the diversity in the behavior of individual cells is
critical for developing new strategies for effectively activating cellular senescence in cance...

## Key facts

- **NIH application ID:** 9842545
- **Project number:** 5R01GM116864-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Galit Lahav
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,266
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842545

## Citation

> US National Institutes of Health, RePORTER application 9842545, Dynamics of Cellular Senescence in Single Cells (5R01GM116864-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842545. Licensed CC0.

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