Mechanisms of vascular dysfunction in acute systemic inflammation

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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 the overarching goal of this research program, which is to better understand mechanisms that affect acute endothelial-mediated vascular dysfunction with the overall intent of being able to identify and treat patients with acute vasculopathy during systemic inflammation to improve clinical outcomes.