# Sphingolipid signaling in age-associated vascular pathology

> **NIH NIH R56** · BOSTON CHILDREN'S HOSPITAL · 2020 · $362,850

## Abstract

Age-related decline in vascular function is a key factor in decreased organ function, vitality,
resistance to stress and increased morbidity/ mortality from cardiovascular and inflammatory
diseases. Our laboratory has made long-standing contributions in the areas of two lipid mediators
– namely, sphingosine 1-phosphate (S1P) and prostacyclin (PGI2), which regulate vascular system
and inflammatory processes. Our recent data suggest that age-dependent decline in S1P and PGI2
signaling axes contribute to vascular dysfunction and disease, thereby contributing to age-related
functional decline in organs. Specifically, S1P signaling shifts from homeostatic to pro-
inflammatory and injurious states during aging. Clinical studies show that attenuated S1P and
PGI2 signaling axes contribute to increased incidence of cardiovascular disease. This proposal is
based on the premise that that dysregulation of lipid mediator signaling pathways are important in
age-related inflammatory and cardiovascular diseases that lead to significant functional decline,
mortality and morbidity. The central hypothesis of the proposal is that decreased vasculoprotective
S1P pathway in the endothelium contributes to age-associated vascular dysfunction and disease.
Such age-associated processes affect the heterogenous vascular endothelium of aorta, retina and
liver in a specific, mechanistically-tractable way to attenuate organ function. We aim to define the
transcriptome of heterogenous endothelial cells from liver, retina and aorta of the mouse during
aging. Similar analysis will also be done from aged mice in which S1PR1 signaling pathway in
the endothelium is attenuated by genetic means. Second, we will define the mechanisms by which
PGI2 signaling in the endothelium synergizes with the S1PR1 to enhance vasculoprotective
signaling and promote vascular health. Third, we will elucidate the mechanisms by which age-
dependent induction of S1PR2 antagonizes S1PR1 and induce vascular dysfunction and
inflammation. Mouse genetic models as well as pharmacological inhibitors of S1PR2 will be
tested to determine their utility in the treatment of age-related vascular dysfunction and disease.
These studies are anticipated to lead to new insights by which lipid mediator signaling pathways
contribute to age-dependent vascular dysfunction and disease, which could ultimately lead to novel
therapeutic strategies to combat age-related organ dysfunction and decline.

## Key facts

- **NIH application ID:** 10253131
- **Project number:** 1R56AG069825-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Timothy Tun Hla
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,850
- **Award type:** 1
- **Project period:** 2020-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253131

## Citation

> US National Institutes of Health, RePORTER application 10253131, Sphingolipid signaling in age-associated vascular pathology (1R56AG069825-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10253131. Licensed CC0.

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