Acute lung injury (ALI) causes major morbidity and mortality in the United States. Recent data indicate a genetic component to ALI susceptibility. A better understanding of these genetic risk factors would offer mechanistic clues to ALI pathogenesis and potentially stimulate investigation of novel therapeutic avenues. In addition, identification of specific, individualized risk factors for ALI might allow future personalized therapy. Our preliminary data indicate that ANGPT2 (angiopoeitin-2) is a candidate gene associated with the development of ALI following severe trauma. The ALI-associated variant we identified and validated is intronic, and has no known function. However, this variant tags the same haplotype block identified by an independent group, providing a strong rationale to further investigate the locus for functional effects. The goals of this proposal are 1) to resequence the LD block of ANGPT2 in a subgroup of subjects who developed ALI and use advanced computational analysis to identify potential functional variants;2) to genotype ANGPT2 variants in a large cohort of critically ill trauma subjects at risk for ALI, and test the associations between genotype and ALI and genotype and plasma protein (ANG-2) level;and 3) to test other angiopoietin pathway members (ANGPT1, TIE1, TIE2, and VEGFA) for association between genotype and ALI, both individually or through interactions with each other. Completion of this project will provide the candidate with advanced training and critical experience in cohort study design and conduct;tailoring genetic analysis at the gene and pathway level;applying advanced bioinformatic and computational techniques to identify functional sequences and test for gene-gene interaction;and applying causal pathway model analysis to determine the contribution of intermediate variables such as plasma protein level. The candidate has assembled a rich mentoring committee spanning expertise in patient-oriented research, molecular and genetic epidemiology, genomics, bioinformatics, and molecular biology. In addition, she is taking advantage of Penn's outstanding educational opportunities through a Master's in Translational Research. The proposal maps a clear plan to allow the candidate to become an independent clinical investigator in patient-oriented translational research. Acute lung injury causes significant morbidity and mortality in the United States. This research will provide new information about genetic risk factors for ALI, and will provide the primary investigator necessary training in cohort study design and novel methodologies to test for gene function and multigenic interaction.

Public Health Relevance

Acute lung injury causes significant morbidity and mortality in the United States. This research will provide new information about genetic risk factors for ALI, and will provide the primary investigator necessary training in cohort study design and novel methodologies to test for gene function and multigenic interaction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL102254-03
Application #
8242724
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
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
$137,052
Indirect Cost
$10,152
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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
Meyer, Nuala J (2013) Future clinical applications of genomics for acute respiratory distress syndrome. Lancet Respir Med 1:793-803

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