The candidate, Dr. Laine Murphey, is a board certified internist and a pharmacologist experienced in studies of cardiovascular physiology. He seeks to continue to progress to independence as a patient-oriented researcher in the field of hypertension through a mentored career development plan that includes bedside research, laboratory studies and a focused curriculum in biostatistics, genetics and study design. The program will take place at Vanderbilt University, which has an historic and strong commitment to the mentored training of clinical researchers. The General Clinical Research Center at Vanderbilt provides the ideal environment for the proposed human studies. Research: Bradykinin, a cardioprotective peptide hormone, is a vasodilator and a natriuretic. In humans, bradykinin contributes to the acute hemodynamic effects of ACE inhibitors, a widely used class of drugs. Studies suggest that endogenous bradykinin may be decreased in human hypertension and that it is modulated by salt-status, ethnic and genetic factors. To date, human studies of systemic bradykinin have been confounded by difficulties in measuring this rapidly metabolized peptide. Prior assays have relied on non-specific radioimmunoassay techniques. Recently, we studied the human in vivo metabolism of systemic bradykinin and identified BK1 -5 as the major stable plasma metabolite of bradykinin. To accurately measure bradykinin and BK1-5, we have developed highly specific and sensitive liquid chromatography-mass spectroscopy assays for these two peptides. Together, these advances in the field now provide powerful methods to determine the role of systemic bradykinin in cardiovascular homeostasis. In this application, I propose to use these new tools to test directly the hypothesis that systemic bradykinin is decreased in hypertension and that it is modulated by genetic, ethnic and environmental factors. The implementation of these studies in a mentored environment, together with participation in directed course work, will provide the applicant with the tools to become an independent patient-oriented researcher.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004445-04
Application #
6648435
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M1))
Program Officer
Schucker, Beth
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$149,591
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
LeFebvre, Jean; Shintani, Ayumi; Gebretsadik, Tebeb et al. (2007) Bradykinin B(2) receptor does not contribute to blood pressure lowering during AT(1) receptor blockade. J Pharmacol Exp Ther 320:1261-7
Pretorius, Mias; Luther, James M; Murphey, Laine J et al. (2005) Angiotensin-converting enzyme inhibition increases basal vascular tissue plasminogen activator release in women but not in men. Arterioscler Thromb Vasc Biol 25:2435-40
Nieman, Marvin T; Warnock, Mark; Hasan, Ahmed A K et al. (2004) The preparation and characterization of novel peptide antagonists to thrombin and factor VIIa and activation of protease-activated receptor 1. J Pharmacol Exp Ther 311:492-501
Murphey, Laine J; Williams, Myles K; Sanchez, Stephanie C et al. (2004) Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. Anal Biochem 334:266-75
Pretorius, Mias; McFarlane, Julie A; Vaughan, Douglas E et al. (2004) Angiotensin-converting enzyme inhibition and smoking potentiate the kinin response to cardiopulmonary bypass. Clin Pharmacol Ther 76:379-87
Summar, Marshall L; Gainer, James V; Pretorius, Mias et al. (2004) Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension 43:186-91
Pretorius, Mias; Murphey, Laine J; McFarlane, Julie A et al. (2003) Angiotensin-converting enzyme inhibition alters the fibrinolytic response to cardiopulmonary bypass. Circulation 108:3079-83
Sawathiparnich, Pairunyar; Murphey, Laine J; Kumar, Sandeep et al. (2003) Effect of combined AT1 receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin Endocrinol Metab 88:3867-73
Murphey, Laine J; Morrow, Jason D; Sawathiparnich, Pairunyar et al. (2003) Acute angiotensin II increases plasma F2-isoprostanes in salt-replete human hypertensives. Free Radic Biol Med 35:711-8
Rosenbaum, David A; Pretorius, Mias; Gainer, James V et al. (2002) Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator release, in response to bradykinin. Arterioscler Thromb Vasc Biol 22:1023-8

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