# Defining and manipulating quiescence associated DNA damage resistance in single cells

> **NIH NIH R00** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $245,000

## Abstract

Project Abstract
Defining and manipulating quiescence associated DNA damage resistance in single cells
The goal of this proposal is to study the phenomena of quiescence as it exists in tumors and
relate this state to chemoresistance. All solid tumors are a heterogenous mix of proliferating
and quiescent cells and many studies on different tumors have determined the quiescent
population to be therapy resistant. Defining which quiescent states contribute to this resistance
and identifying tool compounds to modulate the quiescent state is therefore of great interest. I
will use a novel panel of live cell proliferation reporters derived from classical
immunohistochemical markers of proliferation to study the nature of quiescent states and
directly relate these quiescent states to DNA damage responses at the single cell level. This
study will be carried out in 2- and 3D culture (Aim 1), where we have the genetic and chemical
control to precisely relate DNA damage responses to quiescent states, and later taken in vivo
(Aim 3) to mouse tumor models. Complementing these more observational aims, I will
establish a novel screening tool to identify molecules that specifically modify the
chemoresistance of quiescent cells using a fate tracing approach (Aim 2). This project will
describe the diversity of quiescent states and their inter-relationships, directly relate quiescence
to chemoresistance, and identify tool compounds to manipulate this phenotype.
 This proposal draws on my analytical skills developed as a graduate student working on
yeast stress signaling and as a postdoc over the last two years studying determinates of p53
regulation in normal tissues and tumors. I will apply the single cell techniques and
computational approaches I have learned to study the basic biology underlying quiescence and
chemoresistance in tumors and to identify small molecules that perturb this resistance. In the
mentored phase of this grant I will work under the supervision of my co-mentors Dr. Lahav and
Dr. Weissleder, who are experts on the core focus of my proposal: single cell responses to
genotoxic therapy. During this phase, I will gain the technical skills in cell culture, imaging,
small molecule screening, and mouse work and the professional skills and profile to obtain an
independent academic research position. For the initial phase, I will be embedded in the
department of Systems Biology at Harvard Medical School, a world class research center for the
study of complex quantitative phenotypes and surrounded by clinicians and academics working
on cancer, among other problems. This proposal will complete my transition into a cancer
biologist and provided me with a bridge to an independent research career studying cancer.

## Key facts

- **NIH application ID:** 9850214
- **Project number:** 5R00CA207727-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jacob Stewart-Ornstein
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,000
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850214

## Citation

> US National Institutes of Health, RePORTER application 9850214, Defining and manipulating quiescence associated DNA damage resistance in single cells (5R00CA207727-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9850214. Licensed CC0.

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