Program Director/Principal Investigator (Last, First, Middle): BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE Gandley, Robin E. Assistant Professor eRA COMMONS USER NAME (credential, e.g., agency login) ROBIN_GANDLEY EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) California University of Pennsylvania University of Maryland University of Pittsburgh B.S. Ph.D. Postdoctoral 1984-1988 1988-1993 1993-1999 Chemistry Toxicology Vascular Biology / Reproductive Physiology A. Personal Statement My research interests focus on the impact of metals on the cardiovascular health and reproductive status of women. Work is currently focused on pregnancy and the impact of oxidative stress, due to altered metal metabolism and antioxidant status, on the vascular adaptation to pregnancy. The physiological adaptation to pregnancy results in dramatic alterations in the maternal cardiovascular system. Cardiac output, effective renal plasma, and glomerular filtration rate increase by 40-80%, while blood pressure and peripheral vascular resistance decline. Failed vascular adaptation has been associated with numerous complications of pregnancy, including gestational hypertension and preeclampsia. Currently my efforts have been focused upon examining the impact of low levels of the antioxidant vitamin C, on the vascular changes in pregnancy as well as pregnancy outcome. An understanding of the interactions of metals (zinc, copper, and iron) and antioxidants in the circulation is critical to understanding the role of oxidative stress in the vascular pathologies associated with numerous complications during pregnancy. Among these complications is preeclampsia, a hypertensive disorder of human pregnancy which is thought to include both abnormalities in placentation and maternal vascular adaptation and function. I have recently become very interested in an as yet uncharacterized subgroup of women diagnosed with preeclampsia with low placental growth factor. I utilize numerous in vitro and animal models along with clinical and biochemical studies to examine different aspects of these questions. I have many years of experience designing studies to examine mechanistic questions in women with preeclampsia and normal pregnancies, and more recently have directed our attention to the postpartum period and beyond. I will provide the expertise for the analysis of platelets, and inflammatory and red blood cell function in clinical samples and assessment isolated vascular tissue for specific mechanisms as they relate to pregnancy and preeclampsia, and post-partum vascular disfunction. I have focused on reproductive toxicology related to metals and pregnancy since my graduate work at the University of Maryland at Baltimore under the direction of Dr. Ellen Silbergeld. As a post-doctoral fellow, I focused this research on the vascular system and hypertensive mechanistic studies. I have significant experience using both patient samples and animal models to examine the impact of reduction in circulating ascorbate (vitamin C) on vascular function and pregnancy outcome. Consumption of antioxidants and increased inflammatory processes including increased circulating levels of myeloperoxidase and uric acid are current focuses of my laboratory. B. Positions and Honors Positions and Employment 1987-1988 Student Internship, Department of Energy, Bruceton, PA 1989-1990 Laboratory Manager, Department of Biochemistry, University of Maryland. 1989-1993 Research Assistant, Program in Toxicology, University of Maryland 1993-1999 Postdoctoral Fellow, Department of Obstetrics/Gynecology and Reproductive Sciences, University of Pittsburgh PHS 398/2590 (Rev. 06/09) Page Biographical Sketch Format Page Program Director/Principal Investigator (Last, First, Middle): 1999-2000 1999-Present 2000-2002 2002-Present Honors 1984-1988 1988 1987-1988 1995 1996-1997 Research Assistant Professor, Department of Obstetrics/Gynecology and Reproductive Sciences, University of Pittsburgh Assistant Investigator, Magee-Womens Research Institute Assistant Professor, Department of Obstetrics/Gynecology and Reproductive Sciences, University of Pittsburgh Assistant Professor, Department of Environmental and Occupation Health, University of Pittsburgh Alumni Scholarship, California University of Pennsylvania Academic Achievement Award, Analytical Chemist of Pittsburgh Student Internship, Department of Energy Irene McClenahan Young Investigator Award, Magee-Womens Hospital Individual National Research Service Award (NIH) National Institutes of Environmental Health Sciences "Lead Exposure and Vascular Function during Pregnancy” (1 F32 ES 05717-01 TOX) C. Selected peer-reviewed publications Most relevant to the current application 1. Weissgerber TL, Gandley RE, McGee PL, Spong CY, Myatt L, Leveno KJ, Thorp JM, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Tolosa JE, Saade G, and Sorokin Y. (2013) Haptoglobin phenotype, preeclampsia risk and the efficacy of vitamin C and E supplementation to prevent preeclampsia in a racially diverse population. PLoS One 8(4): e60479. PMCID: PMC3616124 2. Powers RW, Roberts JM, Plymire D, Pucci D, Datwyler S, Laird D, Sogin D, Gandley RE. (2012) Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: Type 1 verse type 2 preeclampsia? Hypertension 60:239-246. PMID:22647886 3. Weissgerber TL, Roberts JM, Jeyabalan A, Powers RW, Lee M, Datwyler SA, Gandley RE. Haptoglobin phenotype, angiogenic factors and preeclampsia risk. Am J Obstet Gynecol. 2012;206(4):358.e10358.e18. NIHMS350011. 4. Laughon SK, Catov J, Provins T, Roberts JM, Gandley RE. (2009) Elevated first-trimester uric acid concentrations are associated with the development of gestational diabetes. Am J Obstet Gynecol. 201(4):402.e1-5. PMCID: PMC2774120 5. Laughon, SK, Catov, J, Roberts JM, Gandley, RE. (2011) First trimester uric acid and adverse pregnancy outcomes. Am J Hypertension published online 20 January. NIHMS 270916 6. Gandley RE, Rohland J, Zhou Y, Shibata E, Harger GF, Rajakumar A, Kagan VE, Markovic N, Hubel CA. (2008) Increased myeloperoxidase in the placenta and circulation of women with preeclampsia. Hypertension. 52(2):387-393. PMCID: PMC2735015 7. Gandley RE, McLaughlin MK, Koob TJ, Little SA, and McGuffee LJ. (1997) Contribution of condroitindermatan sulfate-containing proteoglycans to the function of rat mesenteric resistance arteries. Am J Physiol. 273 42):H953-H960. 8. Raman KG, Gandley RE, Rohland J, Zenati MS, and Tzeng E. (2010) Early hypercholesterolemia contributes to vasomotor dysfunction and injury associated atherogenesis that can be inhibited by nitric oxide. J. Vas. Surg. Published online 14 December. 9. Kagan VE, Tyurin VA, Borisenko GG, Fabisiak JP, Hubel CA, Ness RB, Gandley RE, McLaughlin MK, and Roberts JM. (2001) Mishandling of copper by albumin: Role in redox-cycling and oxidative stress in preeclampsia plasma. Hyperten Preg. 20(3):221-241. 10. Gandley RE, Tyurin VA, Huang W, Arroyo A, Daftary A, Harger G, Jiang J, Pitt B, Taylor RN, Hubel CA, Kagan VE. (2005) S-Nitrosoalbumin-mediated relaxation is enhanced by ascorbate and copper: Effects in pregnancy and preeclampsia. Hypertension. 45(1):21-27. Additional recent publications of importance to the field (in chronological order) PHS 398/2590 (Rev. 06/09) Page Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): 1. Shvedova AA, Tyurina YY, Gorbunov NK, Tyurina YY, Gorbunov NV, Tyurin VA, Castranova V, Ojimba J, Gandley R, McLaughlin MK, Kagan VE. (1999) tert-Butyl hydroperoxide/hemoglobin-induced oxidative stress and damage to mesenteric smooth muscle cells: Different effects of nitric oxide and nitrosothiols. Am J Biochem Pharmacol. 57:989-1001. 2. Gandley RE, Pearce LL, Han W, Wasserloos K, Stitt M, Kanai AJ, McLaughlin MK, Pitt BR, Levitan ES. (2000) Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein. PNAS. 97(1):477-482. 3. Gandley RE, Conrad KP, McLaughlin MK. (2001) Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats. Am J Physiol Regul Integr Comp Physiol. 280(1):R1R7. 4. Gryzunov YA, Arroyo A, Vigne JL, Zhao Q, Tyurin VA, Hubel CA, Gandley RE, Vladimirov YA, Taylor RN, Kagan VE. (2003) Binding of fatty acids facilitates oxidation of cysteine-34 and converts copperalbumin complexes from antioxidants to prooxidants. Arch Biochem Biophys. 413(1):53-66. 5. Powers RW, Gandley RE, Lykins DL, Roberts JM. (2004) Moderate hyperhomocysteinemia decreases endothelial-dependent vasorelaxation in pregnant but not nonpregnant mice. Hypertension. 44(3):327333. 6. Ramirez RJ, Hubel CA, Novak J, DiCianno JR, Kagan VE, Gandley RE. (2006) Moderate ascorbate deficiency increases myogenic tone of arteries from pregnant but not virgin ascorbate-dependent rats. Hypertension. 47(3):454-460. 7. Gandley, RE, Jeyabalan, A, Desai, K, McGonigal, S, Rohland, J, and DeLoia, JA. (2010) Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model. Am J Physiol Regul Integr Comp Physiol. 298(5) R1249-1256. PMCID: PMC2867518 D. Research Support. Ongoing Research Support P01 HD30367-06 Hubel (PI) 04/01/2008 - 03/31/2013 No Cost Extension NIH/NICHD Mechanisms of Preeclampsia: Impact of Obesity, Project IV (Gandley, Robin E.) “Myeloperoxidase in obesity-mediated inflammation/oxidative stress in pregnancy.” The goal of this project is to identify redox-cycling mechanisms present early in pregnancy that lead to oxidative stress and produce markers of oxidant damage that are associated with preeclampsia in overweight and obese women. The project focuses on the inflammatory cell product myeloperoxidase. Role: Subproject PI Pending PO1 HD030367 Hubel (Pl) 04/01/2013 – 03/31/2018 NIH/NICHD Pregnancy Adaptation and Maternal Cardiovascular Health Project III titled “Placental growth factor: Preeclampsia mechanisms and cardiovascular risk”. The goal of this project is to characterize a subset of women with preeclampsia identified by low placental growth factor at 18-24 weeks of gestation. Role: Subproject PI Completed Research Support 5 R01 CA90787-06 Yalowich (PI) 07/26/2007 – 05/31/2012 NIH/NCI Mechanisms and Prevention of Etoposide-Induced Leukemia The central hypothesis of this study is that redox cycling of VP-16 initiated by myeloperoxidase (MPO) amplifies the genotoxicity and carcinogenicity of this agent in myeloid precursors, which contain high MPO activity. Dr. Gandley will provide ascorbate dependent rat and oversee treatment of these rats with etoposide and varied levels of ascorbate. *Magee-Womens Research Institute & Foundation Subcontract 5 P01 HD30367-06 Roberts (PI) 01/01/2002 - 12/31/2006 NIH/NICHD Preeclampsia: Mechanisms and implications post-pregnancy PHS 398/2590 (Rev. 06/09) Page Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): The overall goal of this program project grant is to extend ongoing studies of abnormal cytotrophoblast invasion and its relevance to preeclampsia to address the potential interactions of maternal constitutional factors and fetal signals in the genesis of preeclampsia. Specifically, Project 4 (Gandley, PI) entitled "Mediators of Vascular Dysfunction in Preeclampsia”. The goal of this project is to investigate potential mechanisms underlying the vascular dysfunction that occurs during and after preeclampsia. Inactivation of nitric oxide (NO) by reactive oxygen species, especially superoxide (O2.-), is an important mechanism of vascular dysfunction in several diseases. We propose two phenomena associated with preeclampsia, namely 1) plasma factors interacting with the AT1 receptor, and 2) sub-optimal ascorbate reserves operate in tandem to increase the prevalence of oxidative reactions within the vasculature. In turn, this leads to effective deficiency of NO, through oxidative degradation of NO and/or impaired vascular response to NO. Role: Sub-project PI Abbott Laboratories Roberts (PI) 03/19/2008 – 03/18/2010 Investigation of Blood and Urine Biomarkers for Preeclampsia and Other Diseases of Pregnancy, Circulation and Renal Function The objective of this study was to generate data on the suitability of MPO, PLGF and sF1t-1 as biomarkers for the diagnosis and prognosis of preeclampsia in urine and plasma. Role: Co-I PHS 398/2590 (Rev. 06/09) Page Continuation Format Page