# NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS

> **NIH NIH K08** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $145,664

## Abstract

Project Summary
 The studies proposed for this K08 application will use unique approaches to examine the effects of
sphingolipid metabolism on the mediator of flow-induced vasodilation (FID) within the human vasculature.
Recently it has been shown that ceramide, a bioactive sphingolipid known to be elevated in the plasma of
patients with cardiovascular disease, is an independent predictor of major adverse cardiovascular events. A
potential way ceramide could adversely affect outcomes is by its recently discovered effect on the mediator of
FID. Arterioles exposed to ceramide dilate in response to flow by generating H2O2, a pro-inflammatory and pro-
atherosclerotic mediator as opposed to nitric oxide (NO), the anti-inflammatory, anti-atherosclerotic mediator
utilized by healthy adults in response to increased flow. On the contrary, sphingosine-1-phosphate (S1P), also
within the sphingolipid family and a metabolite of ceramide, promotes NO-dependent FID. How sphingolipids
affect vasoactive mediators formed during flow and impact vascular homeostasis remains largely unknown.
The aims of this proposal examine how the balance of sphingolipids, also known as the `sphingolipid rheostat,'
influences the generation of a specific FID mediator which will have a profound impact on the formation or
prevention of inflammation and atherosclerosis. Overall this application represents the necessary first step to
define the mechanistic role of sphingolipid metabolism during FID in the human microcirculation.
 The training plan during the award phase will expand my scientific skill set in four ways. First, I will
expand my training and experience using an established human vascular reactivity model to investigate how
sphingolipid metabolism and the S1P:ceramide ratio determine the mediator of FID. Second, during a
sabbatical in the laboratory of Dr. Ruikang Wang, I will receive training in tissue imaging, specifically in vivo
microvascular imaging, with the goal of adapting a new technology (CytoCam) to translate our findings to the
whole human. I will also receive training from Dr. Andrew Morris, in how to measure sphingolipids from small
human samples using liquid chromatography tandem mass spectrometry (LC MS/MS). This instrumentation is
available at MCW but has not been adapted for sphingolipid measurements. Bringing this technology to MCW
will greatly strengthen my research program and support others needing to quantify lipid mediators in small
tissue samples. Third, I will complete formal coursework in biostatistics, grant writing, advanced mass
spectrometry techniques, clinical trial design, and medical imaging. These courses were specifically chosen by
me and my mentoring team to supplement my formal training, and will provide vital knowledge as I continue to
develop into an independent investigator. The fourth component of this training plan involves taking on
leadership roles, such as being a mentor to students, managing an affinity group consisted of clin...

## Key facts

- **NIH application ID:** 10314025
- **Project number:** 5K08HL141562-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Julie K Freed
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $145,664
- **Award type:** 5
- **Project period:** 2018-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314025

## Citation

> US National Institutes of Health, RePORTER application 10314025, NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS (5K08HL141562-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10314025. Licensed CC0.

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