Phone: (706) 721-

Fax: (706) 721-9799

Email: sblack@mcg.edu

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Current Projects | Current Grant Support | Lab | Honors & Awards | Invited Speaker | Selected Publications |

Research in the Black Laboratory focuses on the roles of reactive oxygen species (ROS) in cell signaling and how derangements in ROS generation underlie many pathologic states. These studies impact both ROS mediated signal transduction and nitric oxide synthase (NOS) structure-function biology and are of importance in a number of physiological processes. Clinically, these studies should be importnant in developing intervention directed at various pathophysiological disorders in which redox signaling is thought to play crucial roles. These include pulmonary and systemic hypertension, diabetes, renal failure, atherosclerosis, and stroke. The studies in the Black Laboratory are funded by a number of RO1 awards form the National Institutes of Health (NIH). In addition, the Black lab has active collaborations with research groups at a number of universities including the University of California at San Francisco, University of California at Davis, Northwestern University in Chicago, Northern Illinois University at DeKalb, Wayne State University in Detroit, and the German Hear Center of the State of Bavaria, in Munich, Germany.

Alterations in endothelial NO synthase (eNOS) expression and activity by reactive oxygen species Reactive oxygen species (ROS) are thought to play an important role in the development of endothelial dysfunction. Endothelial dysfunction relates to the inability of a blood vessel to expand properly with the result that blood flow is compromised. Endothelial dysfunction has been associated with a decrease in the activity of endothelial NOS (eNOS). We hypothesize that there is a link between high levels ROS and alterations in eNOS expression and activity. To test this hypothesis we are employing an integrated molecular and biochemical approach. We are delineating the signaling pathways that result in increased production of ROS. To evaluate these signaling pathways we are employing a number of techniques including immunoprecipitation, cellular protein kinase determination, and pharmacological inhibition. We are also utilizing the over-expression of wild type, dominant negative, and constitutively active mutant proteins from both mammalian and adenoviral expression systems to specifically target signaling molecules within the cell. In addition we are using fluorescent imaging analysis to quantitate the changes in ROS. We are also employing eNOS promoter-reporter constructs to determine the cis-elements through which ROS alter eNOS expression with the goal of identifying the trans-acting factors.

Role of reactive oxygen species in the development of pulmonary hypertension of the newborn (PPHN) With the initiation of ventilation and oxygenation at birth, pulmonary vascular resistance decreases and pulmonary blood flow increases. There is evidence that increased endothelial NO synthase (eNOS) gene expression, eNOS activity, and NO production, contribute to these changes. However, in a number of clinical conditions, there is failure of the pulmonary circulation to undergo this normal transition to postnatal life, resulting in persistent pulmonary hypertension of the newborn (PPHN). PPHN complicates more than 5 in 1000 live births and up to 10% of admissions to intensive care units. PPHN causes substantial morbidity and mortality in otherwise normal term infants. It is known that newborns who die of PPHN have decreased endogenous NO production and an increase in circulating endothelin-1 (ET-1) levels. In addition these children have an increase in pulmonary arterial medial smooth muscle cell thickness and extension of muscle to normally non-muscular arteries. The anatomic changes in the pulmonary vessels in newborns with PPHN are thought to be intimately associated with the morbidity and mortality associated with PPHN. However, the mechanisms producing this abnormal smooth muscle cell (SMC) development and the reduction in eNOS gene expression and NO production are not well understood. Using whole animal models as well as cellular and molecular biological techniques we are elucidating the signaling mechanisms through which ET-1 alters SMC growth and elucidating how alterations in SMC signaling can alter gene expression in endothelial cells. We hope that these studies will lead to a better understanding of the mechanisms responsible for the development of PPHN that will in turn may lead to improved treatment strategies for children born with pulmonary hypertension.

Biomechanical forces in vascular remodeling Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Survival for these children has improved although substantial morbidity and mortality occurs even after corrective surgery. This is due, in part, to abnormal pulmonary vascular development. This abnormal vascular growth can persist even after surgical intervention establishes a normal pulmonary blood flow. The factors responsible for the altered pulmonary vascular growth in these children are not well understood. We are trying to understand how this process is regulated since a better understanding of this process could lead to treatment strategies that could prevent the adverse consequences of CHD. We have developed a unique ovine model of CHD with increased pulmonary blood flow. In these lambs there is an increase in both the size and number of the pulmonary vessels by 4-weeks of age. The pulmonary circulation of these lambs is subjected to increased levels of blood flow resulting in increased exposure to the biomechanical forces, fluid shear stress and cyclic stretch. We are testing the hypothesis that the vascular remodeling observed in children with CHD, is due, at least in part, to biomechanical forces increasing the expression of growth factors in the lung that stimulate blood vessel growth.

Reactive oxygen species in perintal-hypoxia ischemia Perinatal hypoxia-ischemia (HI) or "stroke" represents a long-standing, refractory public health problem. The neurologic sequelae of the severe form of this injury include mental retardation, epilepsy, cerebral palsy and blindness. Multiple lines of evidence have established the critical role of nitric oxide (NO) in HI-mediated brain injury in the newborn. In addition, data from our laboratory indicate that the developing brain is more vulnerable to HI injury than the mature brain, due to a deficiency in anti-oxidant enzyme capacity, resulting in a greater susceptibility to oxidative stress. However, how the oxidative stress and NO induced by HI interact to produce injury to the neonatal brain remains unresolved. Studies in the lab are trying to unravel the signaling pathways involved in this process. We are utilizing both whole animal models as well as primary neuronal cultures to investigate these events.

STATUS: P.I.
FUNDING AGENCY: National Heart, Lung, and Blood Institute
TITLE OF AWARD: Role of reactive oxygen species in the
development PPHN
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: April, 2002-September 30, 2007
TOTAL DIRECT COSTS: $800,000

STATUS: P.I.
FUNDING AGENCY: National Heart, Lung, and Blood Institute
TITLE OF AWARD: NO signaling in endothelial cells
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: January 1, 2003-December 31, 2007
TOTAL DIRECT COSTS: $1,524,181

STATUS: P.I.
FUNDING AGENCY: National Heart, Lung, and Blood Institute
TITLE OF AWARD: eNOS dimer disruption and endothelial dysfunction
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: December, 2002-November 30, 2007
TOTAL DIRECT COSTS: $825,000

STATUS: P.I.
FUNDING AGENCY: National Heart, Lung, and Blood Institute
TITLE OF AWARD: Perinatal regulation of endothelial NOS
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: December 1, 2003-November 30, 2007
TOTAL DIRECT COSTS: $900,000

STATUS: P.I.
FUNDING AGENCY: American Heart Association-Pacific Mountain Affiliates
TITLE OF AWARD: Effect of shear stress on VEGF receptor signaling in endothelial cells
TYPE OF AWARD: Grant-In-Aid
PERIOD OF SUPPORT: January1, 2005-December 31, 2007
TOTAL DIRECT COSTS: $180,000

STATUS: P.I.
FUNDING AGENCY: LeDuq Foundation
TITLE OF AWARD: PedCarD
TYPE OF AWARD: Transatlantic Networks of Excellence for Cardiovascular Research Programme
PERIOD OF SUPPORT: October 1, 2005-September 30, 2010
TOTAL DIRECT COSTS: $5, 500,000

STATUS: P.I.
FUNDING AGENCY: National Institute Child Health and Development
TITLE OF AWARD: Neuronal NO synthase in neurotoxicity
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: July 1, 2006-June 30, 2011
TOTAL DIRECT COSTS: $1,250,000

STATUS: Co-Investigator (P.I. Jeffrey Fineman, MD)
FUNDING AGENCY: National Heart, Lung, and Blood Institute
TITLE OF AWARD: Perintal pulmonary hypertension: Developmental mediators
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: July 1, 2003-June 30, 2008
TOTAL DIRECT COSTS: $550,000

STATUS: Co-Investigator
FUNDING AGENCY: National institutes of Health
TITLE OF AWARD: Neural Control of Na Balance in Hypertension
TYPE OF AWARD: RO1
PERIOD OF SUPPORT: September1, 2005-June 30, 2010
TOTAL DIRECT COSTS: $1,000,000

• 1986: Imperial Cancer Research Fund Bursars Award.
• 1990: MRC Fellowship.
• 2004-2006: Co-Chair AHA Lung, Respiration/Resuscitation Study Section.
• 2006: NHLBI Board of Scientific Counselors.
• 2007: Distinguished Faculty Award for Basic Science Research, School of Medicine.

(From 93 total)

Wiseman, D.A, Wells, S.M., Wilham, J., Hubbard, M., Welker, J.E., Black, S.M. (2006) Alterations in zinc homeostasis underlie endothelial cell death induced by oxidative stress from acute exposure to hydrogen peroxide. Am J Physiol Lung Cell Mol Physiol. 292:L165-77.

Wedgwood, S., DeVol, J.M., Grobe, A., Benavidez, E., Azakie, A., Fineman, J.R., Black, S.M. (2007) Fibroblast growth factor-2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension Pediatr. Res. 61:32-32.

Wiseman, D.A, Wells, S.M., Wilham, J., Hubbard, M., Welker, J.E., Black, S.M. (2006) Endothelial response to stress from exogenous zinc (Zn2+) resembles that of NO-mediated nitrosative stress, and is protected by MT-1 overexpression. Am J Physiol Cell Mol Physiol. C555-C568.

Grobe, A.C., Wells, S.M., Benavidez, E., Oishi, P., Azakie, A.,Fineman, J.R., Black, S.M. (2006) Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase. Am J Physiol Lung Cell Mol Physiol. 290: L1069-L1077.

Taldone, F., Tummala, M., Goldstein, E.J., Ryzhov, V., Ravi, K., and Black, S.M. (2005) Studying the S-nitrosylation of Model Peptides and eNOS Protein by Mass Spectrometry. Nitric Oxide. 13:176-187.

Wedgwood, S., Steinhorn, R.H., Bunderson, M., Wilham, J., Lakshminrusinha, S., Brennan, L.A., Black, S.M. (2005) Increased hydrogen peroxide down-regulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol. 289:L660-L666.

Mata-Greenwood E, Grobe A, Kumar S, Noskina Y, Black S.M. (2005) Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-beta 1 and reactive oxygen species: a requirement for NAD(P)H oxidase. Am J Physiol Lung Cell Mol Physiol. 289:L288-L299.

Barrett, D.M., Black, S.M., Todo, T., Schmidt-Ullrich, R.K., and Mikkelsen, R.B. (2005) Inhibition of Protein Tyrosine Phosphatases by Mild Oxidative Stresses is Dependent on S-Nitrosylation. J. Biol. Chem 80:14453-14461.

Wedgwood, S. & Black, S.M. (2005) Endothelin-1 decreases endothelial NOS expression and activity through ETA receptor mediated generation of hydrogen peroxide. Am J Physiol Lung Cell Mol Physiol. 288:L480-L487.

Patil, S., Bunderson, M., Wilham, J., Black, S.M. (2004) An important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol. 287:L1314-L1322.

Ravi, K. Brennan, L.A., Levic, S., Ross, P.A., Black, S.M. (2004) S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc. Natl. Acad. Sci. USA. 101:2619-2624.

Kelly, L.K., Wedgwood, S., Steinhorn, R.H., Black, S.M. (2004) Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase. Am. J. Physiol 286:L984-L991.

Black, S.M., Bekker, J.M., Mata-Greenwood, E., Ovadia, B., Fitzgerald, R.K., Thelitz, S., Gerrets, R., Hendricks-Munoz, K., Fineman, J.R. (2003) Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. Circulation. 108:1646-54.

Mata-Greenwood, E., Meyrick, B., Soifer, S.J., Fineman, J.R., Black, S.M. (2003) Expression of VEGF and its receptors Flt-1 and Flk-1/KDR is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Am. J. Physiol. 285: L222-L231.

Mata-Greenwood, E., Meyrick, B., Fineman, J.R., Black, S.M. (2003) Alterations in TGF-b1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension. Am. J. Physiol. 285: L209-L221.

Khan, Y. & Black, S.M. (2003) Developmental changes in brain antioxidant enzyme activity. Pediatr. Res. 54 :77-82.

Wedgwood, S., Mitchell, C.J., Fineman, J.R., Black, S.M. (2003) Developmental differences in the shear stress-induced expression of endothelial NO synthase: changing role of AP-1. Am. J. Physiol. 284:L650-H662.

Brennan, L.A., Steinhorn, R.H., Wedgwood, S., Mata-Greenwood, E., Roark, E.A., Russell, J.A., Black, S.M. (2003). Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: A role for NADPH oxidase Circ. Res. 92:683-691.

Brennan, L.A., Wedgwood, S., Black, S.M. (2002) The over-expression catalase reduces NO-mediated inhibition of endothelial NO synthase. IUBMB Life. 54:261-265.

Brennan, L.A., Wedgwood, S., Bekker, J.M., Black, S.M. (2002) The over-expression of CuZn-SOD protects NOS III from NO-mediated inhibition. DNA & Cell biology. 21:827-838.

Leach, J.K., Black, S.M., Schmidt-Ullrich, R.K., Mikkelsen, R.B. (2002) Activation of constitutive nitric oxide synthase activity is an early signaling event induced by ionizing radiation. J. Biol. Chem. 277:15400-15406.

Wedgwood, S., Dettman, R.W., Black, S.M. (2001) Endothelin-1 stimulates pulmonary arterial smooth muscle cell proliferation via an induction of reactive oxygen species. Am. J. Physiol. L1058-L1067.

Wedgwood, S., McMullan, D.M., Bekker, J.M., Fineman, J.R., Black, S.M. (2001) Rebound pulmonary hypertension caused by inhaled nitric oxide is blocked by the ETA-type receptor blocker PD156707: A role for reactive oxygen species. Circ. Res. 89:357-364.

Wedgwood, S., Bekker, J.M., Black, S.M. (2001) Shear stress regulation of endothelial NOS in fetal pulmonary arterial endothelial cells involves PKC. Am. J. Physiol. 281:L490-L498.

McMullan, D.M., Bekker, J.M., Parry A.J., Johengen, M.J., Heidersbach, R.S., Kon, A.A., Black, S.M., Fineman, J.R. (2000) Endogenous nitric oxide production after cardiopulmonary bypass (CPB) in lambs with normal and increased pulmonary blood flow. Circulation. 102:SIII 172-1788.

Black, S.M., Bristow, J., Soifer, S.J., Fineman, J.R. (2000) Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr. Res. 47:97-106.

Black, S.M., Heidersbach, R.S., McMullin, D.M., Bekker, J.M., Fineman, J.R. (1999) Rebound pulmonary hypertension caused by inhaled nitric oxide is associated with an inhibition of endothelial NO synthase activity. Am. J. Physiol. 277:H1849-H1856.

Hallmark, O.G., Phung, Y.T., Black, S.M. (1999) Chimeric mutants of neuronal NOS identify different regions of the reductase domain that are necessary for dimerization and activity. DNA and Cell Biol. 18:397-407.

Black, S.M., Johengen, M.J., Soifer, S.J. (1998) Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs. Pediatr. Res. 44: 821-830.

Black, S.M., Fineman, J.R., Steinhorn, R.H., Bristow, J., Soifer, S.J. (1998) Increased endothelial NO synthase expression in lambs with pulmonary hypertension and increased pulmonary blood flow. Am. J. Physiol. 44: H1643-H1651.

Sheehy, A.M., Burson, M.A., Black, S.M. (1998) Nitric oxide exposure inhibits endothelial NOS activity but not gene expression: A role for superoxide. Am. J. Physiol. 274: L833-L841.

Black, S.M., Johengen, M.J., Ma, Z-D., Bristow, J.D., Soifer, S.J. (1997) Ventilation and oxygenation induce endothelial NO synthase in the fetal lung. J. Clin. Invest. 100:1448-1458.

Ferriero, D.M., Holtzman, D.M., Black, S.M., Sheldon, R.A. (1996) Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiology of Disease 3:64-71.

Black, S.M., Bedolli, M.A., Martinez, S., Bristow, J., Ferriero, D.M., Soifer, S.J. (1995) Expression of neuronal nitric oxide synthase corresponds to regions of selective vulnerability of hypoxia-ischemia in the developing rat central nervous system. Neurobiology of Disease 2:145-155.

Black, S.M., Ortiz de Montellano, P.R. (1995) Characterization of rat neuronal nitric oxide synthase expressed in Saccharomyces cerevisiae. DNA and Cell Biol. 14:789-794.

Wilks, A., Black, S.M., Miller, W.L., Ortiz de Montellano, P.R. (1995) Expression and characterization of truncated human heme oxygenase (hHO-1) and a fusion protein of hHO-1 with human cytochrome P450 reductase. Biochemistry 34:4421-4427.

Holtzman, D., Kilbridge, J., Bredt, D.S., Black, S.M., Reichardt, L., Mobley, W. (1994) NOS induction by NGF in the basal forebrain cholinergic neurones: evidence for regulation of brain NOS by a neurotrophin. Neurobiology of Disease 1:51-60.

Black, S.M., Harikrishna, J.A., Szklarz, G.D., Miller, W.L. (1994) The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, P450scc. Proc. Natl. Acad. Sci. USA. 91: 7247-7251.

Brentano, S.T., Black, S.M., Lin, D., Miller, W.L. (1992) cAMP post-transcriptionally diminishes the abundance of adrenodoxin reductase mRNA . Proc. Natl. Acad. Sci. USA. 89:4099-4103.

University of California, San Francisco,
Postdoctoral Training, 1991-1993.
Molecular Endocrinology

University of Edinburgh, Scotland,
Postdoctoral Training, 1989-1990.
Molecular Endocrinology

University of Edinburgh, Scotland,
Ph. D., 1986-1989.
Molecular Pharmacology

University of Edinburgh , Scotland
B.Sc.(Honors) 1982- 1986.
Molecular Biology

Research Chemist - Pharmaceutical Chemistry, University of California, San Francisco, 03/1993-09/1994.

Assistant Professor - Pediatrics University of California, San Francisco, 10/1994-02/1999.

Associate Professor - Pediatrics & Molecular Pharamcology, Northwestern University, 03/1999-06/2003.

Associate Professor - Biomedical & Pharmaceutical Sciences, University of Montana, 07/2003-06/2005.

Associate Professor - Molecular Pharmacology, University of Washington, 07/2003-03/2006.

Professor - Biomedical & Pharmaceutical Sciences, University of Montana, 06/2005-03/2006.

Professor - Obstetrics & Gynecology, Medical College of Georgia, 04/2006-present.

ADMINISTRATIVE APPOINTMENTS
Research

Laboratory Director - Child Health Research Center, University of California, San Francisco, 07/1997-02/1999.

Research Director - Division of Neonatology, Northwestern University 03/1999-06/2003.

Director of Vascular Biology - St. Patrick Hospital, 07/2003-04/2006.

COBRE Group Leader - University of Montana, 07/2004-04/2006.

• 1998-present - Society for Pediatric Research.
• 2000-present - Society for Neuroscience.
• 2000-present - Nitric Oxide Society.
• 2000-present - Oxygen Society
  
• 2002-present - American Society for Cell Biology
• 2002-present - Society for Free Radical Biology & Medicine
• 1999-present - American Heart Association