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Eva Grayck, MD


Professor
Pediatric Critical Care Medicine
Cardiovascular and Pulmonary Research Laboratory

Contact Information:
University of Colorado Denver
Pediatric Critical Care Medicine, Box B131
12700 E. 19th Avenue
Research 2, Room 6121
Aurora,CO  80045
Office: 303-724-5615
Lab: 303-724-5616
Fax: 303-724-5617
E-mail: Eva.Grayck@ucdenver.edu

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Research Interests

As a pediatric physician-scientist, my overall goal is to investigate mechanisms responsible for pulmonary vascular structure and function throughout the stages of life, and to understand how disruption in these processes contribute to pulmonary vascular disease. I have focused predominantly on the contribution of reactive oxygen and nitrogen species and antioxidant systems in the pathogenesis of pulmonary hypertension.  Redox signaling and oxidative stress are fundamental processes that contribute to cellular homeostasis and disease pathogenesis across every discipline in medicine; they have been implicated in cell proliferation, vasoconstriction, inflammation and matrix remodeling in pulmonary hypertension. 

I have developed a particular interest and expertise in the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD or SOD3), which, unlike its expression in most other tissues, is highly expressed in blood vessels. It is increasing clear that alterations in EC-SOD expression and activity contribute to the progression of diseases in humans and animal models, like pulmonary hypertension, characterized by inflammation and fibrosis.  Through collaborative research, we have extended our interest in EC-SOD and redox biology to study other disease processes including pulmonary fibrosis, chronic lung disease of infancy, high altitude illness, acute lung injury and wound healing. We are interested in harnessing our new knowledge on the specific cellular and tissue compartments that are impacted by the disrupted balance in oxidants/antioxidants to apply novel therapeutic strategies for targeted delivery of pharmacologic agents including EC-SOD to the site of injury.

Insufficient vascular EC-SOD in pulmonary hypertension:

In both murine and calf models of PH, we have demonstrated that loss of EC-SOD is critically important to the development of vascular remodeling and pulmonary hypertension through its impact on redox-sensitive signaling pathways.  Our laboratory is now utilizing a series of genetically engineered mice with cell-specific inducible knock-down of EC-SOD or knock-in of a human EC-SOD polymorphism with decreased tissue binding affinity, altering its site specific expression or distribution. We are using models of injury in newborn, immature and adult mice to address processes across the age spectrum. These mice, in conjunction with mice overexpressing lung EC-SOD or lacking total body EC-SOD, enable us to interrogate the role of localized EC-SOD in disease progression.  We are currently testing how low vascular EC-SOD promotes matrix remodeling and inflammation, both central components in pulmonary hypertension and with broad relevance to other vascular and lung diseases.

Epigenetic regulation of EC-SOD in pulmonary arterial hypertension:

To extend our findings from animal models of PH to the human condition, we are currently evaluating EC-SOD levels in the lungs of individuals with end-stage  idiopathic pulmonary hypertension.  We are testing the role of epigenetic mechanisms in the regulation of EC-SOD gene expression in human iPAH, in particular, DNA methylation and histone acetylation of the EC-SOD promoter.  These studies are performed with human tissue and cells provided by the Pulmonary Hypertension Breakthrough Initiative.

Dysregulated miRNAs in acute lung injury:

In a multi-PI bench-to-bedside project, we are evaluating the miRNA profile in both critically ill pediatric patients with acute lung injury and several animal models of acute lung injury to identify dysregulated miRNA that may contribute to pathologic gene expression and poor outcomes.  We have identified two miRNAs that target the ephrin receptor involved in vascular permeability or EC-SOD, and are currently establishing, in mouse models and cell culture experiments, the direct relationship between the two miRNA and our genes of interest. We will use this information to test the feasibility of delivering miRNA mimics or antagonists in a targeted fashion to the pulmonary circulation to protect against pathologic gene expression and lung injury.

Targeted delivery of genes and drugs for pulmonary vascular disease.  I have collaborated with investigators within and outside the institution to test novel drug delivery systems to improve the efficacy and toxicity profile of treatments for PAH.  These delivery systems include PGLA nanoparticles with homing peptides on the surface to selectively target injured blood vessels and liposomes.  Either system can be used for delivery of plasmids, siRNA/miRNA molecules or drugs, and are designed to provide selective tissue delivery and lower dosing.   These tools may overcome the barriers that have limited the efficacy of antioxidant therapies in human disease.  As we understand the importance of the specific localization of EC-SOD in the vasculature, and its role in homeostasis and disease, we hope to design better strategies to restore EC-SOD activity in the appropriate site at the optimal time to improve disease outcomes.