Prostacyclin (PGI2), a derivative of arachidonic acid, plays an important role promoting vascular smooth muscle relaxation and preventing platelet aggregation. The actions are mediated through a poorly understood seven transmembrane domain spanning G-protein coupled receptor (GPCR), the prostacyclin receptor (IP). The clinical importance of this receptor stems from its involvement in cardiovascular diseases such as myocardial infarction, stroke, atherosclerosis, and hypertension. The potential use of prostacyclin in the treatment of pulmonary hypertension, and cancers (colon, breast and lung), is currently being intensely investigated. We have recently discovered eleven human prostacyclin receptor polymorphisms. Furthermore preliminary in vitro studies have revealed abnormal function in one of these polymorphisms (R212H). This has led to the hypothesis that such polymorphisms may play a critical role in cardiovascular disease. Through three Specific Aims the goal of this proposal is to understand the pharmacogenetic importance of hIP polymorphisms and in so doing to determine distinct features of this receptor, which enable it to bind a 20-carbon fatty acid (eicosanoid) and couple it to signal transduction pathways, leading to cardiovascular disease. Genomic screening and sequencing will be used to comprehensively search for new polymorphisms and assess association with clinical cardiovascular disease (Specific Aim #1). Novel polymorphisms found will be tested in vitro using site-directed mutagenesis, and structure-function studies (Specific Aim #2).
Specific Aim #3 will focus on downstream signal transduction pathways in human vascular smooth muscle cells to determine mechanisms for cardiovascular defects. In addition to this proposed collaboration between the Pharmacology, Medicine (Statistics), Vascular Surgery, Cardiology and Pathology Departments here at Dartmouth, strong groups in protein structure-function and signal transduction, will be critical resources for addressing these Specific Aims. Achievement of these aims, should not only improve our understanding of the molecular genetics and structure-function of the prostacyclin receptor, but may also provide the critical biochemical understanding to explain interindividual differences in progress of cardiovascular disease and variable responses associated with prostacyclin analogue treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074190-03
Application #
7036600
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Ganguly, Pankaj
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$312,285
Indirect Cost
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Jin, Yu; Xie, Yi; Ostriker, Allison C et al. (2017) Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response. Arterioscler Thromb Vasc Biol 37:2311-2321
Xiang, Yaozu; Cheng, Jijun; Wang, Dandan et al. (2015) Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 125:3377-87
Xie, Yi; Jin, Yu; Merenick, Bethany L et al. (2015) Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition. Sci Signal 8:ra44
Chakraborty, Raja; Bhullar, Rajinder P; Dakshinamurti, Shyamala et al. (2014) Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor. PLoS One 9:e85937
Obinata, Hideru; Gutkind, Sarah; Stitham, Jeremiah et al. (2014) Individual variation of human S1P? coding sequence leads to heterogeneity in receptor function and drug interactions. J Lipid Res 55:2665-75
Liu, Renjing; Jin, Yu; Tang, Waiho et al. (2014) Response to letter regarding article, ""ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity"". Circulation 130:e72
Moore, Jason H; Hwa, John (2014) Editorial: pharmacogenetics and molecular medicine: ""so close and yet so far"". Curr Mol Med 14:803-4
Vanichakarn, P; Hwa, J; Stitham, J (2014) Cardiovascular pharmacogenetics of antihypertensive and lipid- lowering therapies. Curr Mol Med 14:849-79
Stitham, J; Vanichakarn, P; Ying, L et al. (2014) Cardiovascular pharmacogenetics of anti-thrombotic agents and non-steroidal anti-inflammatory drugs. Curr Mol Med 14:909-31
Tang, Wai Ho; Stitham, Jeremiah; Jin, Yu et al. (2014) Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation 129:1598-609

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