Chronic lung, heart and vascular diseases such as idiopathic pulmonary fibrosis (IPF), idiopathic pulmonary arterial hypertension (IPAH), secondary pulmonary hypertension (SPAH), and left ventricular (LV) and right ventricular (RV) heart failure are significant and common causes of mortality and morbidity. Although the molecular mechanisms of individual diseases have been extensively studied, it is unknown whether the molecular phenotypes and mechanisms are shared across disease and organ boundaries. Our overall objective is to use high throughput approaches and the extensive resources of well-characterized tissues in the University of Pittsburgh Cardiovascular Institute, the Simmons Center for Interstitial Lung Diseases and the Vascular Medicine Institute to identify new molecular phenotypes across and within disease and organ boundaries. To identify such phenotypes we will: 1. Identify tissue molecular signatures by analyzing failing and non-failing human RV tissue in IPAH or SPAH;failing and non-failing human LV tissue;human IPF and control lungs;lungs and pulmonary vessels of patients with IPAH and SPAH;and lung, RV, LV and pulmonary vessels from the same patients from our unique warm autopsy program. We will perform mRNA and microRNA expression profiling, validate key patterns and pathways by high throughput qRT PCR and generate cross organ tissue microarrays to perform high-throughput tissue protein validation and localization. 2. Identify biomarkers of disease presence, stage and outcome, within and across organ and disease boundaries, in easily accessible peripheral blood by analyzing peripheral blood from patients with LV and RV failure, IPAH and IPF. We will perform mRNA and microRNA expression profiles and determine expression patterns that predict disease presence, state and outcome within and across organ and disease boundaries. 3. Generate a disease and mechanism relevant transcriptional map in RV and LV failure, IPAH and IPF by performing an integrated analysis of mRNA and microRNA expression patterns as well as clinical data with the use of advanced computational approaches, followed by cell culture and animal model validations of analytic predictions.

Public Health Relevance

Lung, heart, and vascular diseases are common causes of death that frequently occur in the same patients. They are usually diagnosed and treated as distinct entities, but may share common molecular mechanisms that respond to the same treatments. We will identify these common mechanisms by analyzing patterns of gene expression in different diseases and organs, using advanced molecular and computational techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL108642-04
Application #
8730511
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Eu, Jerry Pc
Project Start
2011-08-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
$497,772
Indirect Cost
$92,518
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Tzouvelekis, Argyris; Herazo-Maya, Jose D; Slade, Martin et al. (2017) Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology 22:486-493
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
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

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