# Senescence dysregulates of inflammation-resolution programs in atherosclerosis

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2022 · $617,817

## Abstract

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Failed
resolution of a chronic inflammatory response is an important driving force in the progression of
atherosclerosis. Resolution is mediated by the critical balance between specialized pro-resolving mediators
(SPMs) such as lipoxins and resolvins and pro-inflammatory factors like leukotrienes (LTs) and prostaglandins
(PGs). Previous work from our lab and others suggest that SPMs are defectively synthesized in plaques and
that restoration of SPMs prevents atherosclerosis progression in mice. Gaps remain in our understanding as to
a) what cellular processes derange the synthesis of SPMs in
protective actions of SPMs in atherosclerosis. Therefore, the
plaques and b) mechanisms associated with the
overall objective of this proposal is to understand
new mechanisms of dysregulated resolution in atherosclerosis and to harness new SPM signaling pathways
towards a novel treatment strategy. Cellular senescence is an irreversible cell cycle arrest that leads to a highly
pro-inflammatory phenotype called the senescence-associated secretory phenotype (SASP). Prominent
features of senescent cells (SCs) include elevated levels of COX2 and PGs and heightened glycolysis. SCs
recently emerged as a driver of plaque necrosis but mechanisms are poorly understood. Our new work
suggests that senescence impairs endogenous resolution programs and that key SPMs can limit the SASP.
We proposed a series of studies to identify the mechanisms associated with senescence and impaired
resolution (Aim I), the link between myeloid senescent cells and SPM formation in plaques (Aim II) and
mechanisms underlying how hypercholesterolemia impacts senescence and SPM synthesis (Aim III). The link
between dysregulated resolution programs and senescence is a completely new and unexplored area of
research that may reveal new treatment strategies for atherosclerosis that are complementary to those that
currently exist.

## Key facts

- **NIH application ID:** 10427260
- **Project number:** 5R01HL153019-03
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** Gabrielle Fredman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $617,817
- **Award type:** 5
- **Project period:** 2020-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427260

## Citation

> US National Institutes of Health, RePORTER application 10427260, Senescence dysregulates of inflammation-resolution programs in atherosclerosis (5R01HL153019-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10427260. Licensed CC0.

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