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.
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.
|Kusko, Rebecca L; Brothers 2nd, John F; Tedrow, John et al. (2016) Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 194:948-960|
|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|
|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|
|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|
|Tzouvelekis, Argyris; Herazo-Maya, Jose D; Slade, Martin et al. (2016) Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology :|
|Rosas, Ivan O; Kaminski, Naftali (2015) Update in diffuse parenchymal lung disease, 2013. Am J Respir Crit Care Med 191:270-4|
|Kim, SungHwan; Herazo-Maya, Jose D; Kang, Dongwan D et al. (2015) Integrative phenotyping framework (iPF): integrative clustering of multiple omics data identifies novel lung disease subphenotypes. BMC Genomics 16:924|
|Bauer, Yasmina; Tedrow, John; de Bernard, Simon et al. (2015) A novel genomic signature with translational significance for human idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 52:217-31|
|Bauer, Yasmina; Nayler, Oliver; Kaminski, Naftali (2015) Reply: the bleomycin model: in pursuit of relevant biomakers. Am J Respir Cell Mol Biol 53:748-9|
|Hidvegi, Tunda; Stolz, Donna B; Alcorn, John F et al. (2015) Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy. J Biol Chem 290:29742-57|
Showing the most recent 10 out of 43 publications