Chronic lung diseases represent a broad spectrum of chronic fibrosing/inflammatory lung conditions that are for the most part poorly responsive to treatment and often fatal. COPD/emphysema is the fourth leading cause of death in the United States and the incidence and rate of death from pulmonary fibrosis is increasing each year. Although progress has been made in interpretation of the clinical, radiological, and pathological features of chronic lung disorders, and progress in determining the pathobiology continues, the causes, biologic mechanisms, and therapeutic options remain obscure. Moreover, predicting individuals or populations at risk for developing any of these complex diseases, at present, is not possible. To address this challenge, we plan to create a genetic, molecular, and quantitative clinical phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. The composite genetic, genomic, and epigenetic signature combined with quantitative clinical phenotypes has the potential to characterize the dynamic biological state of a complex disease and complement existing diagnostic approaches that are reliant on traditional clinical measures of disease. In the proposed project, we plan to extend the scope and impact of the NHLBI Lung Tissue Research Consortium (LTRC) biorepository by creating the Lung Genomics Research Consortium (LGRC), a comprehensive genetic, molecular, and quantitative clinical phenotyping warehouse. Our overall hypothesis is that a genetic, molecular, and quantitative clinical phenotyping warehouse combined with a rich clinical database will enable the lung research community to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. We plan to pursue this hypothesis through the following aims.
Specific Aim 1 : Establish a genetic, genomic, and epigenetic molecular library to complement the existing clinical database in the LTRC.
Specific Aim 2 : Develop a quantitative clinical phenotyping platform using existing LTRC data, as well as an enhanced data set including novel quantitative CT and histology imaging analyses.
Specific Aim 3 : Establish a publicly-accessible database that would integrate the genetic, molecular, and quantitative phenotyping data with the existing clinical data in the LTRC and provide query and data exploration tools that are easily accessible to the lung research community. These discoveries will enable clinicians to: 1) identify individuals at risk of developing chronic lung diseases;2) diagnose these conditions earlier;3) identify novel mechanisms that cause these diseases;4) reclassify disease entities into categories more representative of molecular and cellular pathogenic mechanisms regardless of traditional disease categories;and 5) develop personalized approaches to treatment.

Public Health Relevance

Chronic lung diseases affect a significant portion of the population, the incidence of COPD/emphysema and idiopathic interstitial pneumonia are increasing annually, and COPD is the fourth leading cause of death in the U.S. (www.cdc.gov). Despite major investments that have been made in lung research over the past two decades, these disease remains major public health problems that paradoxically are increasing in prevalence, incidence, and severity. To address this challenge, we plan to create a genetic, molecular, and quantitative phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. These discoveries will enable clinicians to: 1) identify individuals at risk of developing chronic lung diseases;2) diagnose these conditions at an earlier stage;3) identify novel mechanisms that cause chronic lung disease;and 4) eventually develop personalized therapeutic strategies for intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
7RC2HL101715-03
Application #
8305295
Study Section
Special Emphasis Panel (ZHL1-CSR-D (O1))
Program Officer
Gan, Weiniu
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2011-08-15
Budget End
2012-08-31
Support Year
3
Fiscal Year
2010
Total Cost
$1,654,805
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Anathy, Vikas; Lahue, Karolyn G; Chapman, David G et al. (2018) Reducing protein oxidation reverses lung fibrosis. Nat Med 24:1128-1135
Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49
Tzouvelekis, Argyrios; Yu, Guoying; Lino Cardenas, Christian L et al. (2017) SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. Am J Respir Crit Care Med 195:500-514
Tan, Jiangning; Tedrow, John R; Nouraie, Mehdi et al. (2017) Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12. J Immunol 198:2269-2285
Manichaikul, Ani; Sun, Li; Borczuk, Alain C et al. (2017) Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc 14:628-635
Platig, John; Castaldi, Peter J; DeMeo, Dawn et al. (2016) Bipartite Community Structure of eQTLs. PLoS Comput Biol 12:e1005033
Peng, Xueyan; Moore, Meagan; Mathur, Aditi et al. (2016) Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis. FASEB J 30:4056-4070
Begum, Ferdouse; Sharker, Monir H; Sherman, Stephanie L et al. (2016) Regionally Smoothed Meta-Analysis Methods for GWAS Datasets. Genet Epidemiol 40:154-60
Fares, Wassim H; Bellumkonda, Lavanya; Tonelli, Adriano R et al. (2016) Right atrial pressure/pulmonary artery wedge pressure ratio: A more specific predictor of survival in pulmonary arterial hypertension. J Heart Lung Transplant 35:760-7
Fingerlin, Tasha E; Zhang, Weiming; Yang, Ivana V et al. (2016) Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 17:74

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