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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL098362-03
Application #
8240473
Study Section
Special Emphasis Panel (ZHL1-CSR-U (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$131,652
Indirect Cost
$9,752
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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