This proposal describes a 5 year training program for a career in investigative medicine in Pulmonary Diseases with the long term goal of establishing a research program within the field of acute lung injury. The applicant has finished a fellowship in Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh and is currently completing a research fellowship at the University of Pennsylvania. She is currently conducting research in transfusion-mediated acute lung injury, a common problem in the critically ill population. The research focus of this proposal is to elucidate some of the mechanisms by which stored erythrocytes induce lung injury during systemic inflammatory states. The central hypothesis of the proposal is that transfused RBC's directly """"""""activate"""""""" pulmonary endothelial cells and neutrophils through the receptor for advanced glycation endproducts (RAGE) causing lung injury.
In Specific Aim 1, the role of RAGE in endothelial cell activation induced by banked human RBCs will be defined.
In Specific Aim 2, the effects of stored RBCs on neutrophil function in vitro and in vivo will be studied.
In Specific Aim 3, the mechanisms by which stored RBCs induce lung injury during endotoxemia will be explored using mouse models. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures and seminars in lung diseases, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of Lung Research and Vice-chief of the Division of Pulmonary, Allergy and Critical Care Medicine at Penn. He has mentored over 60 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.

Public Health Relevance

Recent epidemiological studies have shown that red cell transfusions are associated with the development of lung injury along with increased morbidity and mortality in the critically ill. The etiology underlying this association remains uncertain. The main goal of this study is to define the mechanism by which red blood cell transfusions induce lung injury in the critically ill. Knowledge derived from these studies may elucidate one mechanism underlying the consequences of red cell transfusion, provide new insight to a common problem in the critically ill, and hopefully lead to strategies to reduce this complication.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-U (O1))
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Colombini-Hatch, Sandra
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Hotz, Meghan J; Qing, Danielle; Shashaty, Michael G S et al. (2018) Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury. Am J Respir Crit Care Med 197:470-480
Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43
Qing, Danielle Y; Conegliano, David; Shashaty, Michael G S et al. (2014) Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation. Am J Respir Crit Care Med 190:1243-54
Mangalmurti, Nilam S; Friedman, Jessica L; Wang, Liang-Chuan et al. (2013) The receptor for advanced glycation end products mediates lung endothelial activation by RBCs. Am J Physiol Lung Cell Mol Physiol 304:L250-63
Mangalmurti, Nilam S; Chatterjee, Shampa; Cheng, Guanjun et al. (2010) Advanced glycation end products on stored red blood cells increase endothelial reactive oxygen species generation through interaction with receptor for advanced glycation end products. Transfusion 50:2353-61