Primary graft dysfunction (PGD) is the most common cause of morbidity and mortality after lung transplantation. Recent data indicate participation of a few specific pathways in acute lung injury models and post-transplant PGD. A better understanding of these specific pathways would offer mechanistic clues to PGD pathogenesis and potentially stimulate investigation of novel therapeutic avenues. In addition, identification o specific, individualized risk factors for PGD might allow future personalized therapy. Our preliminary data indicate that among the top genes identified as having the largest fold differences in PGD compared to control, ANGPT2 a key mediator of vascular inflammation/ permeability demonstrated a 7-fold increase in donors pre- procurement which further increased an additional 10-fold post reperfusion. Given the up-regulation of ANGPT2 gene expression in our transplant cohort prior to harvest, there appears to be unmeasured injury to the lung despite normal physiologic measurements which needs to be further characterized. The long-term objective of our line of research is to understand the mechanism of PGD in human lung transplantation in order to identify strategies to identify donors at risk, prevent recipient death and potentially expand the donor pool through better donor selection and use of ex vivo lung perfusion (EVLP) strategies. Our approach is to use gene expression in donor lung biopsies to predict PGD, and to examine specific inflammatory, innate immunity and vascular permeability pathways involved in PGD of transplanted donors and untransplantable donors placed on EVLP. The central hypotheses are that lung injury occurring in the donor lung prior to reperfusion can be evaluated by gene expression methods to determine PGD risk, identify """"""""low risk"""""""" organs that would have been discarded that can be transplanted, and understand common mechanisms of PGD and recovery on EVLP. 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, expression and pathway level;and applying advanced bioinformatic and computational techniques for pathways analysis and risk prediction. 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, he is taking advantage of Penn's outstanding educational opportunities through a Master's in Clinical Epidemiology. The proposal maps a clear plan to allow the candidate to become an independent clinical investigator in patient-oriented translational research.

Public Health Relevance

Primary graft dysfunction is the most common cause of morbidity and mortality after lung transplantation. The long-term objective of this line of research is to understand the mechanism of PGD in human lung transplantation in order to identify strategies to identify donors at risk, prevent recipient death, potentially expand the donor pool through better donor selection 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 #
1K23HL116656-01
Application #
8424616
Study Section
Special Emphasis Panel (ZHL1-CSR-X (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$160,556
Indirect Cost
$11,707
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Diamond, J M; Shah, R J; Cantu 3rd, E et al. (2016) Survey of Lung Transplant Community's Views on Primary Graft Dysfunction. Am J Transplant 16:724-6
Diamond, Joshua M; Porteous, Mary K; Jackson Roberts 2nd, L et al. (2016) The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia. J Heart Lung Transplant 35:500-7
Cantu, E; Suzuki, Y; Diamond, J M et al. (2016) Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk. Am J Transplant 16:833-40
Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65
Shah, R J; Diamond, J M; Cantu, E et al. (2015) Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation. Am J Transplant 15:2188-96
Young, J C; Chehoud, C; Bittinger, K et al. (2015) Viral metagenomics reveal blooms of anelloviruses in the respiratory tract of lung transplant recipients. Am J Transplant 15:200-9
Cantu, Edward; Shah, Rupal J; Lin, Wei et al. (2015) Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg 149:596-602
Cohen, David G; Christie, Jason D; Anderson, Brian J et al. (2014) Cognitive function, mental health, and health-related quality of life after lung transplantation. Ann Am Thorac Soc 11:522-30
Shah, Rupal J; Emtiazjoo, Amir M; Diamond, Joshua M et al. (2014) Plasma complement levels are associated with primary graft dysfunction and mortality after lung transplantation. Am J Respir Crit Care Med 189:1564-7
Bittinger, Kyle; Charlson, Emily S; Loy, Elizabeth et al. (2014) Improved characterization of medically relevant fungi in the human respiratory tract using next-generation sequencing. Genome Biol 15:487

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