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 prevention for this disease, newer targetedtherapies can improve outcomes by altering vascular tone using prostacyclin (PGI2) analogues, dual endothelin antagonists, or phosphodiesterase - 5 inhibitors. Recent progress inthe understanding of genetic aberrations in PAH suggests 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 PPARy, are down-regulated in patients with PAH. Disruption of PGI2 signaling through the PPARy pathway leads to aberrant cell growth. Our hypothesis proposes that PGI2 can signal through either PGIR or PPARy. We hypothesize that signaling through PGIR results in more prominent effects on vascular tone while PPARy stimulation results in effects onvascular remodeling. This proposal 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 (PPARY) 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 PPARy 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 preliminary work demonstrates that sequence variation in the proximal PGIS promoter region affects promoter activity leading to low PGIS expression. 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 PPARy 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 PPARy pathwaysto 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 PPARy down-regulation.
We have previously demonstrated that two critical modulators of vascular tone and proliferation (PGI2 and PPAR-/) are downregulated in disease. This application utilizes translational murine modeling to examine mechanisms of signaling important to vasculartone and remodeling. Furthermore, studies of patients with the PAH will be performed to examine the relationship of genetic polymorphisms and disease severity, as well as mechanisms of loss of PGI2 and PPARy.
|SchÃ¤fer, Michal; Myers, Cynthia; Brown, R Dale et al. (2016) Pulmonary Arterial Stiffness: Toward a New Paradigm in Pulmonary Arterial Hypertension Pathophysiology and Assessment. Curr Hypertens Rep 18:4|
|Bartels, Karsten; Brown, R Dale; Fox, Daniel L et al. (2016) Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension. Anesth Analg 122:1280-6|
|Voelkel, Norbert F; Tamosiuniene, Rasa; Nicolls, Mark R (2016) Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14:939-51|
|Graham, Brian B; Robinson, Jeffrey C; Tuder, Rubin M (2016) Fatty Acid Metabolism, Bone Morphogenetic Protein Receptor Type 2, and the Right Ventricle. Am J Respir Crit Care Med 194:655-6|
|Horita, Henrick; Wysoczynski, Christina L; Walker, Lori A et al. (2016) Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation. Nat Commun 7:10830|
|PlecitÃ¡-HlavatÃ¡, Lydie; Tauber, Jan; Li, Min et al. (2016) Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension. Am J Respir Cell Mol Biol 55:47-57|
|Keller, Amy C; Knaub, Leslie A; McClatchey, P Mason et al. (2016) Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model. Oxid Med Cell Longev 2016:8524267|
|Stenmark, Kurt R; Frid, Maria; Perros, FrÃ©dÃ©ric (2016) Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH. Circulation 133:1734-7|
|McClatchey, P Mason; Keller, Amy C; Bouchard, Ron et al. (2016) Fully automated software for quantitative measurements of mitochondrial morphology. Mitochondrion 26:58-71|
|Bruns, Danielle R; Buttrick, Peter M; Walker, Lori A (2016) Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy. Am J Physiol Lung Cell Mol Physiol 310:L542-50|
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