The purpose of seeking an Individual Physician Scientist Award is to provide the applicant with research training in Phase 1, under the sponsorship of Dr. Michael J. Dunn (Case Western), that deals with in vitro techniques pertaining to the study of glomerular function. These techniques include: (a) isolation of rat glomeruli, (b) culture of rat glomerular epithelial and mesangial cells, (c) preparation of these cells for electronmicroscopy, and their subsequent identification, (d) analysis of basal and stimulated levels of cyclooxygenase products from freshly isolated glomeruli and glomerular cells in culture by radioimmunoassay and radiometric thin layer chromatography and (e) quantification of angiotensin II (AII) receptor density and affinity in the glomerulus. Additionally, the applicant will learn the extraction and chromatographic procedures required for purification of prostaglandins (PGs) from complex biological fluids. In Phase 2, under the sponsorship of Dr. Heinz Valtin (Dartmouth), these techniques will be applied to the study of glomeruli from pregnant rats, in order to discover a potential role for glomerular cyclooxygenase products, and angiotensin II receptors in the regulation of GFR, ERPF, and renal vascular resistance (RVR). Specifically, the applicant will examine in glomeruli isolated from pregnant rats (a) basal synthetic rates of PGs, (b) Michaelis-Menten kinetics of the cyclooxygenase system, (c) stimulated synthetic rates of PGs by addition of exogenous AII, arginine vasopressin, and norepinephrine, (d) potential production of 2,3-dinor-6keto-PGF1Alpha, (e) possible effects of estradiol and progesterone on PG production by cultured epithelial and mesangial cells, and (f) AII receptor density and affinity. These in vitro approaches will be carried out in conjunction with further studies in the chronically instrumented, conscious rat -- a method in which the applicant is currently expert, and has applied successfully to the investigation of pregnancy -- that utilize cyclooxygenase inhibition and infusions of angiotensin II and norepinephrine in an effort to discover a role for PGs in the modulation of GFR, ERPF, RVR and mean arterial pressure during pregnancy. In summary, this proposal addresses the potential role of PG/AII interactions in the control of glomerular function and blood pressure during pregnancy. A better understanding of the mechanisms that regulate the physiology of pregnancy would undoubtedly facilitate investigations of the pathogenesis of certain conditions that often complicate pregnancy -- e.g., preeclampsia and bilateral renal central necrosis.
| Conrad, Kirk P; Davison, John M (2014) The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin? Am J Physiol Renal Physiol 306:F1121-35 |
| Conrad, Kirk P; Shroff, Sanjeev G (2011) Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep 13:409-20 |
| Conrad, Kirk P (2011) Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol 301:R267-75 |
| Conrad, Kirk P (2010) Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension 56:2-9 |
| McGuane, Jonathan T; Debrah, Julianna E; Debrah, Dan O et al. (2009) Role of relaxin in maternal systemic and renal vascular adaptations during gestation. Ann N Y Acad Sci 1160:304-12 |
| Jeyabalan, Arundhathi; Conrad, Kirk P (2007) Renal function during normal pregnancy and preeclampsia. Front Biosci 12:2425-37 |
| Conrad, Kirk P; Jeyabalan, Arun; Danielson, Leslie A et al. (2005) Role of relaxin in maternal renal vasodilation of pregnancy. Ann N Y Acad Sci 1041:147-54 |
| Conrad, K P; Novak, J; Danielson, L A et al. (2005) Mechanisms of renal vasodilation and hyperfiltration during pregnancy: current perspectives and potential implications for preeclampsia. Endothelium 12:57-62 |
| Davison, John M; Homuth, Volker; Jeyabalan, Arun et al. (2004) New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 15:2440-8 |
| McLaughlin, M K; Conrad, K P (1995) Nitric oxide biosynthesis during pregnancy: implications for circulatory changes. Clin Exp Pharmacol Physiol 22:164-71 |
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