Alpha-1 antitrypsin deficiency (A1 AT), an autosomal recessive genetic disease that is associated with a variable risk of COPD, and Sarcoidosis, a systemic disease characterized by the formation of granulomatous lesions especially In the lungs, liver, skin, and lymph nodes that leads to a dramatically heterogeneous set of clinical manifestations, differ in etiology and clinicl presentation but share a variable and unpredictable course. To improve disease classification, facilitate biomarker discovery and accelerate advent of novel therapy an integrative approach that combines the results of clinical studies with molecular phenotyping results is required. The Sarcoidosis and A1 AT Genomics and Informatics Center (SAGIC) will facilitate this process by addressing the following objectives for the NHLBI Genomic Research In A1 AT and Sarcoidosis (GRADS) program: 1) Coordination of Clinical Centers activities that include patient recruitment and phenotyping and biospecimen collection. 2) Performance of transcriptome and microbiome analyses of the samples obtained by the Clinical Centers, 3) Data analysis and integration, 4) Dataset preparation for deposit in the NHLBI BloLINCC repository. The objectives will be addressed through two research projects. Project 1: A1 AT microbiome - will address the hypothesis that shifts in the lung microbiome determine the extent of lung involvement In A1 AT and that they are reflected in mRNA and microRNA changes in surrogate tissues, and Project 2: Novel molecular phenotypes in Sarcoidosis - will address the hypothesis that systemic Inflammation as reflected in gene expression changes in PBMC Is indicative of disease extent, microbiome shifts and granuloma molecular networks.

Public Health Relevance

Alpha 1 antitrypsin (A1AT) and sarcoidosis are lung diseases characterized by unpredictable course and potential significant morbidity. This research proposes transforming the understanding of these diseases by serving as a hub for NHLBI Genomic Research in A1 AT and Sarcoidosis (GRADS) program by performing two study wide research protocols: A1 AT Metagenome and New Sarcoidosis Molecular Phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL112707-01
Application #
8265053
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F5))
Program Officer
Punturieri, Antonello
Project Start
2012-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$2,068,387
Indirect Cost
$593,639
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hamzeh, Nabeel; Li, Li; Barkes, Briana et al. (2016) The effect of an oral anti-oxidant, N-Acetyl-cysteine, on inflammatory and oxidative markers in pulmonary sarcoidosis. Respir Med 112:106-11
Strange, Charlie; Senior, Robert M; Sciurba, Frank et al. (2015) Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol. Ann Am Thorac Soc 12:1551-60
Jara, Paul; Calyeca, Jazmin; Romero, Yair et al. (2015) Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype. Am J Physiol Lung Cell Mol Physiol 308:L511-22
Rosas, Ivan O; Kaminski, Naftali (2015) Update in diffuse parenchymal lung disease, 2013. Am J Respir Crit Care Med 191:270-4
Moller, David R; Koth, Laura L; Maier, Lisa A et al. (2015) Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol. Ann Am Thorac Soc 12:1561-71
Braun, Nicole A; Celada, Lindsay J; Herazo-Maya, Jose D et al. (2014) Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity. Am J Respir Crit Care Med 190:560-71
Liao, Serena G; Lin, Yan; Kang, Dongwan D et al. (2014) Missing value imputation in high-dimensional phenomic data: imputable or not, and how? BMC Bioinformatics 15:346
Zhang, Yingze; Kaminski, Naftali (2012) Biomarkers in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 18:441-6