Support from this K23 Career Development Award will provide Dr. Mikacenic with the opportunity to meet her long-term goal of becoming an independently funded translational investigator at the crossroads of human immunology and critical illness. This proposed project focuses on heterogeneity in T-regulatory cell responses drawing on Dr. Mikacenic's previous experience in cellular and molecular laboratory based techniques. Importantly, it provides the fundamental training needed for Dr. Mikacenic to pursue her goal of outcomes research directly relevant to acute respiratory distress syndrome (ARDS) in patients. This will be accomplished in the short term by expert mentorship, didactic coursework, and a project designed to implement her knowledge in a practical manner. In terms of the research environment, the University of Washington provides a rich academic environment as one of the most highly NIH-funded research institutions in the country. The Division of Pulmonary and Critical Care Medicine has produced many successful independently funded researchers particularly in the area of critical illness. Dr. Mikacenic has amplified this environment by collaborating with the T-regulatory cell experts at the Benaroya Research Institute, a non-profit biomedical research facility with international recognition. Most importanty, she has surrounded herself with a strong mentorship team with expertise in critical illness, immunology, genetics and epidemiology to obtain her goals. The research in this grant focuses on prolonged mechanical ventilation in ARDS. This syndrome carries high mortality and can lead to significant disability in survivors, particularly those will long intensive care unit stays In this patient oriented research plan, Dr. Mikacenic aims to define the role of human T-regulatory cells, an immunosuppressive lymphocyte, in prolonged mechanical ventilation in ARDS. This cell type is thought to improve resolution of lung injury in mouse models but human research is lacking. She will determine if T-regulatory cell quantity or function is associated with prolonged mechanical ventilation. Additionally, Dr. Mikacenic will take advantage of common and functional genetic variation in human Toll-like receptor 1 (TLR1) as a mechanism by which the function of these cells may be altered. The findings of these studies will have direct patient impact. In a syndrome with few treatment options to improve patient outcomes, improved T- regulatory cell responses may provide a novel treatment strategy to dampen over-exuberant inflammation. The genetic nature of these studies may also further personalize treatment strategies for subpopulations of ARDS patients.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) is an inflammatory syndrome of the lung occurring in response to severe illness but there are few interventions positively affecting patient outcomes. In patients with sepsis and ARDS, we have found a common genetic difference that is associated with death from this condition and we believe this genetic difference may alter how a certain anti-inflammatory cell of the immune system, a T- regulatory cell, works to resolve injury to the lung. Therefore, we hope to understand the how genetic differences in people may affect how these cells function and harness this knowledge towards new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1)
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Reineck, Lora A
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Mikacenic, Carmen; Moore, Richard; Dmyterko, Victoria et al. (2018) Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia. Crit Care 22:358
Morrell, Eric D; Wiedeman, Alice; Long, S Alice et al. (2018) Cytometry TOF identifies alveolar macrophage subtypes in acute respiratory distress syndrome. JCI Insight 3:
Orlov, Marika; Dmyterko, Victoria; Wurfel, Mark M et al. (2017) Th17 cells are associated with protection from ventilator associated pneumonia. PLoS One 12:e0182966
Esposito, Anthony J; Bhatraju, Pavan K; Stapleton, Renee D et al. (2017) Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. Crit Care 21:304
Mikacenic, Carmen; Price, Brenda L; Harju-Baker, Susanna et al. (2017) A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis. Am J Respir Crit Care Med 196:1004-1011
Long, Anna E; Tatum, Megan; Mikacenic, Carmen et al. (2017) A novel and rapid method to quantify Treg mediated suppression of CD4 T cells. J Immunol Methods 449:15-22
Hahn, William O; Mikacenic, Carmen; Price, Brenda L et al. (2016) Host derived biomarkers of inflammation, apoptosis, and endothelial activation are associated with clinical outcomes in patients with bacteremia and sepsis regardless of microbial etiology. Virulence 7:387-94
Mikacenic, Carmen; Hansen, Elizabeth E; Radella, Frank et al. (2016) Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome. Crit Care Med 44:496-502
Robinson-Cohen, Cassianne; Katz, Ronit; Price, Brenda L et al. (2016) Association of markers of endothelial dysregulation Ang1 and Ang2 with acute kidney injury in critically ill patients. Crit Care 20:207
Mikacenic, Carmen; Hahn, William O; Price, Brenda L et al. (2015) Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness. PLoS One 10:e0141251

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