# Genome maintenance and cell fate responses

> **NIH NIH P01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $434,428

## Abstract

ABSTRACT - PROJECT 3
 DNA damage and its sequelae are now recognized as major drivers of aging. However, many
questions remain regarding the nature of age-promoting DNA damage, the role of mutations in non-cancer
age-related pathology, and how genomic damage and its sequelae drive age-related phenotypes and
pathologies. Project 3 will determine -- in depth, breadth and primarily at the level of cellular responses -- how
genes that participate in genome maintenance assure tissue health and ultimately longevity. The primary (but
not the only) consequence-generating cell fate responses are cellular senescence and apoptosis. The extent
to which cells in aged organisms acquire mutations and/or experience these cellular consequences due to
DNA damage are poorly understood. We will explore the relationship between DNA damage-induced cell fates
and mutations (with Project 2), molecular consequences of DNA damage (with Project 1), and human gene
variants implicated in longevity (with Project 4). Specifically, we will determine cell fate responses of cells
carrying genome maintenance genotypes associated with premature and delayed aging identified by Projects 1
and 4, focusing on multifunctional repair genes that participate in repair processes important for relieving
replication or transcriptional stress. We will interrogate cellular senescence and apoptosis (and other forms of
cell death), and markers of cell function. With Project 2, we will determine whether some genomic changes
(e.g., aneuploidy, INDELS) preferentially elicit one cell fate over another. We will use simple and complex
culture systems, focusing primarily on the skin, brain and liver and use single cell analyses to determine how
different types of DNA damage affect cellular heterogeneity and variability. We will also determine the cellular
responses to genotoxic stress in the backgrounds of genome maintenance genotypes and in response to
genomic damage in wild-type and mutant mouse models, and naturally aged mice. We will exploit our mouse
model in which senescent cells can be eliminated, or use pharmacological means to eliminate senescent cells,
to determine how modifying this cell fate affects hallmarks of aging. Finally, once we have a candidate list of
human gene variants associated with aging and longevity from Project 4, we will use human embryonic stem
cells harboring these variants to assess the cells and their differentiated progeny for their cell fate responses to
genomics stressors. Together, this Project will allow us to integrate the genomic and cellular responses to
DNA damage during natural, accelerated and delayed aging in mouse and human cells, and provide
mechanistic bases for predicting the efficacy of interventions into aging phenotypes and pathologies.

## Key facts

- **NIH application ID:** 9964617
- **Project number:** 5P01AG017242-25
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Judith Campisi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,428
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964617

## Citation

> US National Institutes of Health, RePORTER application 9964617, Genome maintenance and cell fate responses (5P01AG017242-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964617. Licensed CC0.

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