Prostacyclin Synthase and Receptors in Pulmonary Arterial Hypertension

  • Geraci, Mark, (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is characterized by elevations in pulmonary artery pressure, vascular remodeling, and hyperproliferation of endothelial cells. While there is no cure or preventative treatment for this disease at present, newer targeted therapies can improve outcomes by altering vascular tone using prostacyclin (PGI2) analogues, dual endothelin antagonists, or phosphodiesterase - 5 inhibitors. Recent progress in the understanding of genetic aberrations in PAH suggests that it is a complex disorder and that modifier genes are potentially involved in mediating increased susceptibility and severity. Two genes that affect the level of prostacyclin signaling, prostacyclin synthase (PGIS) and the nuclear receptor PPAR?, are down- regulated in patients with PAH. Disruption of PGI2 signaling through the PPAR? pathway leads to aberrant cell growth. Our hypothesis proposes that PGI2 can signal through either PGIR or PPAR?. We hypothesize that signaling through PGIR results in more prominent effects on vascular tone (RV pressures, RV hypertrophy) while PPAR? stimulation results in more effects on vascular remodeling. The research proposed here focuses on 1) the effectiveness of augmenting signaling through the two different PGI2 receptors as a treatment to reverse remodeling of both smooth muscle and endothelial cells in PAH (PPAR?) or vascular tone (PGIR), 2) the potential modifier gene role of the PGIS and gene in conferring a predisposition to PAH and an increased likelihood of developing severe PAH, and 3) the mechanism of PGIS and PPAR? loss of expression in human disease. We will use two sophisticated murine modeling systems generated by our group to dissect the relative contribution of the two receptors to the development of PAH. Our proposed pre-clinical rat studies establish the effectiveness of a combinatorial treatment using a PGI2 analogue and a PPAR? agonist may quickly translate in to a human combined drug trial. Our preliminary work demonstrates that sequence variation in the proximal PGIS promoter region affects promoter activity leading to low PGIS expression, thus establishing a predisposition to PAH. We will sequence the PGIS promoters from familial pulmonary hypertension, correlating specific haplotypes with disease on-set, severity, and morbidity. Finally, because epigenetic silencing and chromosomal loss are common mechanisms of gene expression down-regulation, we will determine if either is responsible for PGIS or PPAR? down-regulation in micro-dissected PAH lesions using methylation specific PCR (MSP) and fluorescence in situ hybridization (FISH). Specific Aim 1: Delineate the contributions of PGIS and PPAR? pathways to PAH susceptibility and severity. Specific Aim 2: Define transcriptional activity of PGIS promoter sequence variations in relevant primary cells types, and their frequency and correlation in a defined human population. Specific Aim 3: Determine if methylation silencing and/or allelic loss account for PGIS and PPAR? down- regulation in micro-dissected lesions from patients with severe PAH. PUBLIC HEALTH RELEVANCE: Pulmonary Arterial Hypertension (PAH) is a very serious lung disease in which blood pressure in the lung's pulmonary artery increases making the heart work harder to pump blood into the lung. PAH is very rare with an annual incidence of 1 to 2 per million and occurs more often in women. While there is no cure or preventative treatment, newer targeted therapies can improve outcomes. This project will help us understand how current treatments are reducing the changes in the pulmonary artery that lead to the high blood pressure and may lead to newer therapies that are more effective in controlling the progression and severity of PAH.
StatusFinished
Effective start/end date9/15/088/31/13

Funding

  • National Institutes of Health: $114,750.00
  • National Institutes of Health: $114,750.00
  • National Institutes of Health: $115,125.00
  • National Institutes of Health: $18,090.00
  • National Institutes of Health: $321,518.00

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Epoprostenol Receptors
Pulmonary Hypertension
Peroxisome Proliferator-Activated Receptors
Epoprostenol
Modifier Genes
Pulmonary Artery
Blood Vessels
Down-Regulation
prostacyclin synthetase
Therapeutics
Methylation
Endothelial Cells
Phosphodiesterase 5 Inhibitors
Pressure
Lung

Keywords

  • Medicine(all)