# Mechanisms of vascular dysfunction in acute systemic inflammation

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $432,500

## Abstract

PROJECT SUMMARY:
The systemic inflammatory response syndrome, driven by a host’s response to inflammatory triggers such as
foreign pathogens and cytokines, causes significant dysfunction in the vasculature. This dysfunction is due to
the loss of homeostatic mechanisms within the endothelium and manifests as intravascular fluid loss, abnormal
leukocyte trafficking, disrupted coagulation and altered vascular tone. Despite its overwhelming and obvious
negative effect on patients and their outcomes, targeting vascular pathways, such the vasodilator nitric oxide,
has not yielded successful results. The failure of such trials, along with the general absence of effective
treatments for acute systemic inflammation, has left clinicians with no therapeutic options beyond supportive
care. Unfortunately, the root cause of vascular dysfunction in acute systemic inflammation remains completely
unknown and with many unanswered questions. What spatiotemporal protein interactions or metabolic pathways
contribute to or counterbalance the dysfunction? Does the presence of vasculopathy lead to specific genomic or
proteomic signatures, known as endotypes, and how can they be modeled? What unique endothelial targets
exist that can be utilized to improve vascular function and restore homeostasis? To answer these questions and
any further that will arise, our research program will focus on three integrated themes. Theme one will explore
molecular mechanisms that dysregulate endothelial homeostasis during acute inflammation. Mechanisms such
as direct protein-protein interactions, mitochondrial dysfunction and reactive oxygen species signaling will be
explored using a variety of techniques including genetic modification, glycolytic and oxidative stress capacity and
proximity ligation assays. Theme two will focus on modeling endothelial dysfunction utilizing overlapping
procedures in both animals and humans to identify consistent patterns. This theme will test animal models of
systemic inflammation in combination with acutely ill human patients using non-invasive vascular reactivity
techniques, such as laser doppler perfusion monitoring, coupled with genomic and proteomic signatures. In
addition, the use of microfluidic devices (i.e. tissue-on-a-chip) will create a bridge between the more adaptable
animal models and the non-adaptable human patient populations to test if a synthetic human system will correlate
with data derived from mechanism driven animal studies. The third theme will focus on drug discovery. This
theme will use the biochemical mechanisms found in the prior themes to help discover endothelial-specific,
targeted treatments. Use of cell-penetrating peptides coupled to novel compounds or peptide sequences will
allow cell permeation to the target of interest. In addition, testing of therapies used in chronic vascular dysfunction
will be examined to determine if similar mechanisms can be tempered in acute systemic vasculopathy. These
integrated themes support t...

## Key facts

- **NIH application ID:** 10029318
- **Project number:** 1R35GM138191-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ryan J Stark
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,500
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029318

## Citation

> US National Institutes of Health, RePORTER application 10029318, Mechanisms of vascular dysfunction in acute systemic inflammation (1R35GM138191-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029318. Licensed CC0.

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