Pulmonary arterial hypertension (PAH) is a serious lung disease characterized by proliferative changes in the small pulmonary arteries that leads to vessel narrowing, elevated pulmonary artery pressure and right heart failure. There is growing evidence that proliferative lesions in the lungs of PAH patients are akin to neoplasia, with monoclonal expansion and genetic instability. Supporting this, we recently identified chromosomal abnormalities in endothelial cells from PAH lungs, including mosaic deletions of the X-chromosome in 16% of female cases. We have also found a surprisingly high frequency (32%) of very skewed X-inactivation patterns, which may represent monoclonality or reactivation of the inactive X-chromosome. In this study we will conduct a detailed analysis of X-inactivation in primary cell cultures and uncultured lung tissue to distinguish these two hypotheses and also identify whether cases with X-chromosome deletion have lost the active or inactive X. Allele-specific expression of X- linked genes will be analyzed using next generation sequencing and in situ hybridization will be performed to visualize X-chromosome copy number and XIST expression, a marker of X-inactivation, in uncultured tissue sections. Determining the frequency of monoclonality is critical to the neoplasia-like model for PAH pathogenesis and other abnormalities of the X-chromosome may in part explain the higher incidence in females than males.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a serious, potentially life-threatening lung disorder with a complex etiology. This study will use lung tissue from patients with PAH who have undergone lung transplantation to characterize changes in the X-chromosome that occur during the course of the disease. The long-term goal is to understand how PAH develops and design more effective treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Research Grants (R03)
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Special Emphasis Panel (ZHL1-CSR-Q (S1))
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Moore, Timothy M
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Drake, Kylie M; Federici, Chiara; Duong, Heng T et al. (2017) Genomic stability of pulmonary artery endothelial colony-forming cells in culture. Pulm Circ 7:421-427
Drake, Kylie M; Comhair, Suzy A; Erzurum, Serpil C et al. (2015) Endothelial chromosome 13 deletion in congenital heart disease-associated pulmonary arterial hypertension dysregulates SMAD9 signaling. Am J Respir Crit Care Med 191:850-4
Federici, Chiara; Drake, Kylie M; Rigelsky, Christina M et al. (2015) Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 192:219-28
Duong, Heng T; Comhair, Suzy A; Aldred, Micheala A et al. (2011) Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension. Pulm Circ 1:475-86