Current Research and Scholarly Interests
The pathological changes in the lung blood vessels that cause right-sided heart failure include loss of the distal microcirculation and obliterative proliferative changes occluding the lumen of larger arteries. Our goal is to learn how we can activate lung vascular developmental programs to regenerate lost microvessels and to reverse the obliterative changes. Over the past decade our research has led to four novel compounds in clinical trial or being positioned for clinical trial.
Our research projects have explored the link between the genetic mutation causing loss of function of bone morphogenetic protein receptor (BMPR) 2 and perturbation of Wingless (Wnt) signaling, PPARg mediated gene regulation, RNA translation, cross-talk with other cell surface receptors (PDGF, RAGE) and structural and functional derangement of the pulmonary circulation. We also address how viruses perturb microRNA function and how this might lead to the activation and production of neutrophil elastase in the vessel wall, and we use microfluidics to establish lung vascular and inflammatory cells that are transformed or abnormally expanded.
New NIH funded research uses induced pluripotent stem cells in collaboration with the laboratory of Dr. Joseph Wu and next generation sequencing in collaboration with the laboratory of Dr. Michael Snyder. Our team compares endothelial cells (ECs) derived from induced pluripotent stem cells (iPSC) with native ECs, to improve our understanding of pulmonary hypertension. Towards this goal, we are comparing gene variants (by Exome/whole genome sequencing), epigenetic changes (DNA methylation, by Methyl-Seq) and RNA expression (by RNA-Seq) in iPSC-ECs derived from skin fibroblasts or blood cells,, iPSCs derived from pulmonary arterial EC, with native PAECs. from the same PAH patients or controls. Our second goal is to use iPSC-ECs derived from blood or skin of PAH patients to correct gene variants and to screen novel therapies to determine whether the EC functions of these cells normalize.
We also have an NIH Translational Program Project with the laboratories of Drs. Richard Bland and Mark Nicolls to address the vulnerable microcirculation in pulmonary hypertension, chronic lung disease of prematurity and lung transplant rejection and to work toward translation of novel therapies including the elastase inhibitor elafin. Together with the Nolan, Robinson, Utz and Kodadek Groups on an NIH Proteomics Initiative we address autoimmunity and its relationship to the development of pulmonary hypertension. We use high throughput immunophenotyping and mass element flow cytometry (CYTOF) to identify abnormalities in the immune system and in the response to viral infection.
Other investigator-initiated research focuses on the pivotal role of PPARg as a transcription factor activated by BMPR2, and its novel role in DNA damage and repair.. These studies led to investigations linking p53, with PPARg and the DNA repair machinery and others, that have uncovered a role for amphetamine-stimulated G-protein Coupled Receptor (GPCR) signaling in amplifying DNA damage.
We are engaged in creating genetically modified mice with conditional cell-specific deletion of genes, fate mapped reporter geenes to trace lineage and heterozygosity to understand vascular and cardiac phenotypes. We are then positioned to use these mice to reverse disease. We address many features of altered signaling related to the BMP receptor (R2) mutated in familial forms of pulmonary hypertension. Recently we have shown that alterations in normal functioning of BMPR2 impairs elastin fiber assembly and increases susceptibility to degradation by elastase. Well-assembled elastin maintains the integrity and distensibility of vessels and prevents abnormal proliferation of underlying smooth muscle cells and fibroblasts.
