Pulmonary Arterial Hypertension (PAH) is a poorly understood, devastating disease. Lungs of patients with PAH exhibit dysregulated endothelial proliferation, in contrast to the monolayer endothelial cell architecture found in normal pulmonary arteries. This dysregulated endothelial proliferation manifests as neointima and plexiform lesions. Plexiform lesions from patients with Idiopathic Pulmonary Arterial Hypertension (IPAH) have been shown to be monoclonal and to exhibit microsatellite instability, two hallmarks of cancer. In research proposed here, we seek to characterize somatic genetic alterations in neointima and the plexiform lesion through a genome-wide search made possible by recent advances in microarray technology. This proposal will thereby extend the cancer paradigm of IPAH.
The specific aims of this proposal are to characterize genetic alterations in proliferative endothelium from IPAH lungs using SNP arrays, and to verify and generalize these alterations using currently accepted standard cytogenetic techniques. The proposed genome-wide search is feasible because of recent developments in the technology and application of single nucleotide polymorphism (SNP) microarrays. We and others have demonstrated that genetic alterations such as loss of heterozygosity (LOH), gene amplification or deletion, aneuploidy, and uniparental isodisomy can be efficiently characterized across the entire genome using SNP arrays. Furthermore, these analyses can be conducted with the quantity and quality of genomic DNA that can be recovered from cell culture and from specially prepared fixed lung tissue sections subject to laser capture microdissection. Our research results will have a large impact on the conduct of future research into pulmonary hypertension. We anticipate that these exploratory studies will form the basis for an R01 funded research program investigating the functional consequences of the pathogenetics. Furthermore, I believe that novel treatment opportunities for IPAH will flow from the etiological understanding this research will produce. Treatment concepts have recently been expanded beyond vasodilatation to include a small number of antiproliferative agents. Our elucidation of IPAH etiology will allow us to leverage the """"""""target-based"""""""" treatment paradigm employed in cancer therapy, and this targeted selection of antiproliferative agents for IPAH treatment will improve the likelihood that a lasting cure can be achieved.
Our discovery of recurrent patterns of genetic alteration in Idiopathic Pulmonary Arterial Hypertension lesions will direct us to disease modifying genes associated with the development of IPAH, and fundamentally change the understanding of IPAH pathobiology. Individuals suffering from PAH have limited treatment options, and by improving our understanding of this disease we hope to stimulate new and nascent treatment strategies.
| Nakachi, Ichiro; Rice, Jessica L; Coldren, Christopher D et al. (2014) Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. Cancer Prev Res (Phila) 7:255-65 |
| Aldred, Micheala A; Comhair, Suzy A; Varella-Garcia, Marileila et al. (2010) Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 182:1153-60 |
