With a progressively aging population, the cost of managing cardiovascular disease among the estimated 79,400,000 affected individuals, will account for increasing proportions of our health budget. Early identification and intervention in those at greatest risk, may assist in reducing the associated morbidity and mortality. The human prostacylin receptor has recently been implicated in knockout mice studies, and cyclooxygenase-2 inhibitor clinical trials (e.g. Vioxx"), as important in inhibiting atherosclersosis and thrombosis, two major causes of cardiovascular disease. Based upon these observations, we hypothesize that naturally occurring genetic mutations in the human prostacyclin receptor may predispose individuals to disease. We have recently identified 31 genetic variants of the human prostacyclin receptor from screening 1,434 cardiovascular and control patients. Our hypothesis is that such variants are associated with clinical progression of cardiovascular disease. Through three specific aims we propose to study the wild type and variant receptors at multiple levels. Molecular and biochemical studies (Specific Aim 1) will dissect the structure and function of the human prostacyclin receptor determining the critical structural components required for binding and activation and how these may be influenced by the variants. With the patients' clinical data (Specific Aim 2), we will correlate genetic variants to the development of coronary artery disease (atherosclerosis). A focus will additionally be placed on the African American population where we have uncovered some potentially important variants located at highly conserved positions. The third Specific Aim has arisen from our preliminary observation that vascular smooth muscle cells have a prostacyclin- induced prostacyclin release (positive feedback) mechanism which appears to be important in preventing proliferation and dedifferentiation (cause of restenosis and intimal hyperplasia) in a paracrine fashion. This appears to be largely independent of the known prostacyclin receptor protein kinase A signaling pathway. Preliminary evidence that novel signaling through ERK and Akt is required, will be intensively explored. To ensure a thorough, meticulous, accurate, and ethical approach to our studies, they will be conducted in close collaboration with our Institutional Review Board, Computational Genetics Laboratory, Biostatistician, Cardiology Department, and Vascular Surgery Department. In this "postgenomic era" we are now poised to develop critical insights into the structure and function of the prostanoid receptors and their relationship to cardiovascular disease, through the study of genetic variants.

Public Health Relevance

Cardiovascular disease remains the single greatest cause of morbidity and mortality in the USA. With the recent sequencing of the human genome we are now poised to uncover many of the predisposing genetic contributors to cardiovascular disease. We have strong evidence that the prostacyclin receptor and its signaling pathways will play a critical role in the prevention of atherosclerosis, and as such, dysfunctional genetic variants will predispose patients to accelerated disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074190-08
Application #
8206742
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Kindzelski, Andrei L
Project Start
2003-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$409,613
Indirect Cost
$162,113
Name
Yale University
Department
None
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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