# In Vitro and In Vivo Biology of Telomere Stress Induced Senescence

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $51,752

## Abstract

PROJECT SUMMARY
Senescent cells have been implicated as drivers of aging and age-associated diseases. Senescent cells have
sustained some form of stress that causes irreversible cell-cycle arrest, and these cells avoid apoptosis. These
cells have a hyper-metabolic phenotype and secrete cytokines and chemokines resulting in the senescence
associated secretory phenotype (SASP). The SASP contains multiple inflammatory components which
promotes tissue dysfunction. These observations have been the impetus to develop senolytic drugs. These
drugs are designed to cause the selective apoptosis of senescent cells and several senolytics have already
entered clinical trials for potential use in idiopathic pulmonary fibrosis, osteoarthritis, chronic diabetes, etc.
Many of these senolytic drugs have been developed via a candidate approach where drugs that were initially
developed for the treatment of cancer are repurposed for the clearance of senescent cells. These drugs,
unfortunately, have both on-target and off-target dose-limiting side effects such as thrombocytopenia and
trabecular bone loss. Therefore, there is a need to develop senolytic drugs that target a specific underlying
vulnerability of senescent cells without affecting healthy cells. In this project, we have performed an unbiased
CRISPR-based, whole genome synthetic lethality screen to identify genes when knocked out, are lethal in the
setting of a cell that has undergone telomere-induced senescence yet are well-tolerated when knockout in the
context of a healthy, non-senescent cell. Through this screen, we identified that genetic alterations in ER stress
pathways are specific vulnerabilities of senescent cells. Specifically, the targets ER-resident proteins, PARP16
and BIP, which were identified in the CRISPR screen, modulate ER stress pathways. Therefore, we
hypothesize that due to their high secretory burden, senescent cells are particularly vulnerable to alterations in
ER stress pathways.
 We propose to investigate the following: (1) Identify and characterize the set of genes which when
knocked out in senescent cells cause the specific death of these cells without affecting the function of healthy
cells; (2) Understand whether senescent cells that undergo telomere induced senescence have higher levels of
ER stress and whether alterations in these pathways affect the viability of senescent cells and the production
of SASP components; (3) Understand whether telomere-induced senescence affects the function of post-
mitotic cells such as cardiomyocytes and in turn, whether cardiomyocyte senescence affect heart function.
 This proposal will therefore lead to a better understanding of the unique molecular vulnerabilities of
senescent cells and clarify the molecular underpinnings of how cells maintain a state of senescence.
Successful completion of this proposal will provide a foundation for the development of senolytics to treat a
variety of aging-associated diseases. Finally, this proposal will p...

## Key facts

- **NIH application ID:** 10465569
- **Project number:** 1F30AG077834-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shohini Kalyani Ghosh-Choudhary
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465569

## Citation

> US National Institutes of Health, RePORTER application 10465569, In Vitro and In Vivo Biology of Telomere Stress Induced Senescence (1F30AG077834-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10465569. Licensed CC0.

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