DNA modifications in primary pulmonary hypertension

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DESCRIPTION (provided by applicant): The pathobiology of primary pulmonary hypertension (PPH) is associated with changes in expression of about 300 genes. Understanding the molecular events driving abnormal transcription in PPH is critical for improved diagnosis and design of new therapies, but the mechanism(s) is currently unknown. Several emerging lines of evidence support a new concept for transcriptional regulation in PPH. Chief among these is the finding that oxidative DNA damage is present in cells from PPH lung tissue. Recent studies in human cortical neurons show that age-related accumulation of oxidative DNA damage in selectively vulnerable promoters impairs transcription of genes involved in neuronal survival and plasticity. Conversely, experiments in cultured rat pulmonary vascular cells suggest that targeted nucleotide specific base modifications in promoter sequences, caused by growth stimuli found in PPH, facilitate induction of VEGF expression. Integrating these disparate lines of evidence leads to a new concept for the abnormal gene expression in PPH. We propose that the equilibrium density and nucleotide-specific patterns of oxidative modifications in promoter sequences govern increases and decreases in gene expression in PPH. Two aims will be addressed: Aim 1 will test the hypothesis that promoters of genes that are up- or down-regulated in PPH lung tissue display changes in the equilibrium density of oxidative promoter modifications that are predictive of the transcriptional state of the gene; and, Aim 2 will test the hypothesis that nucleotide-specific pattern of oxidative base modifications in the VEGF promoter in lung DNA from PPH patients with increased VEGF mRNA expression differs from that in lung DNA from patients with pulmonary arterial hypertension secondary to chronic obstructive lung disease wherein VEGF expression is decreased. These "translational" studies are significant and innovative because the concept that the position and density of oxidative "modifications" in promoters are determinants of gene expression is entirely new. If evidence for this regulatory mechanism extends to PPH, it will point to novel diagnostic strategies founded on detection of sequence-specific oxidative DNA modifications and to DNA damage and repair pathways as potential targets for intervention. Finally, if DNA is oxidatively threatened in an acquired disease like PPH, this will point to unappreciated mechanisms of somatic mutation, age-related vasculopathies and other disorders wherein genes targeted by ROS play a pivotal role.