Integrative Multiomics and Systems Biology of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a lung disease characterized by narrowing of the pulmonary arteries causing hemodynamic resistance which eventually leads to right heart failure and death. Current therapies mainly act through vasodilation but none reverse the underlying vascular remodeling characteristic of PAH. A deeper understanding of the molecular and cellular mechanisms of PAH is needed to bridge this translational gap. The goal of this dissertation is to investigate the transcriptional alterations in PAH lungs using integrative multiomics to identify and prioritize candidate genes, pathways, and cell types implicated in PAH.First, we identified reprogramming of genes and pathways in various cell types in the lungs of two commonly used rat models of PAH, namely Sugen-hypoxia (SuHx) and monocrotaline (MCT), using single-cell RNA sequencing (scRNAseq). We found that genes dysregulated in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and GWAS variants. We further identified candidate drugs predicted to reverse the dysregulated gene programs. This study revealed the distinct and shared reprogramming of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning. Next, we dissected the human PAH lung transcriptome at the tissue level using an innovative network and systems biology methods on a well-powered RNA sequencing dataset of human PAH lungs. We discovered many DEGs and pathways in human PAH lungs at the tissue level, and through integration with clinical data and PAH GWAS, our network analysis revealed co-expressed gene modules that are not only associated with PAH diagnosis and severity, but also risk of PAH implicating their causal role in PAH pathogenesis. Key driver analysis utilizing a comprehensive gene regulatory network of the human lung identified and prioritized candidate genes. Furthermore, we integrated the tissue-level networks with scRNAseq to uncover the specific cell types mediating the tissue-level gene programs. Overall, this integrative multiomics and systems biology study revealed and prioritized the dysregulation of many genes, pathways, and cell types in the lungs of PAH animal models and patients, thereby opening new avenues for therapeutic targeting.