Faculty Profile: Barbara Stonestreet, MD

Barbara Stonestreet, MD
Professor of Pediatrics
Pediatrics
Work: (401)-274---1122-x47429
Dr. Stonestreet is the director of the Fellowship in Neonatal-Perinatal Medicine at Women & Infant's Hospital. She oversees the fellowship recruitment, orientation, and guides the fellows during their training. She also coordinates the department weekly Perinatal Management Conference.

Dr. Stonestreet has been involved in studies to understand brain development and the pathogenesis of brain injury in the fetus and neonate.

Biography

Barbara S. Stonestreet, M.D., is a Professor of Pediatrics at Brown Medical School. She is a Staff Neonatologist and Director of the Fellowship Program in Neonatal-Perinatal Medicine at Women & Infants Hospital of Rhode Island. She received her Bachelor's Degree in Biology and German from New York University (New York, New York), and her M.D. from Tufts University (Boston, Massachusetts). Dr. Stonestreet then continued her training in pediatrics at Stanford University School of Medicine (Stanford, California) and Boston University School of Medicine (Boston, Massachusetts). She completed her Fellowship in Neonatal-Perinatal Medicine at Brown University and Women & Infants Hospital of Rhode Island. Dr. Stonestreet has been listed in Best Doctors in America and has served as an active member of the National Institutes of Child Health and Human Development Study Section from 1991-1995. Dr. Stonestreet also served as a member of the Editorial Board of the Journal of Pediatrics from 1990-1997. She is a member of the Society for Pediatric Research, Perinatal Research Society, American Pediatric Society, Society for Neuroscience, and Society for Gynecologic Investigation. Dr. Stonestreet has more than 95 publications in peer-reviewed journals, on various aspects of neonatology and perinatology, including cerebral circulation, fetal blood-brain barrier permeability, and fetal brain injury.

Institutions

Wih

Research Description

The laboratory under the leadership of Dr. Barbara Stonestreet is focusing on two main focuses:

[1] She is the principal investigator on a NIH RO1 proposal entitled: Cytokines and Blood-Brain Barrier Permeability in the Ovine Fetus. The proposal tests the hypothesis that specific cytokines cross the intact and injured blood-brain barrier in the fetus to damage the brain. Hypoxic-ischemic brain injury is the single most important neurologic problem in the perinatal period. In utero hemodynamic abnormalities possibly in association with elevated pro-inflammatory cytokines (cytokines) such as IL-1β, IL-6, and TNF-α predispose to brain injury, particularly in premature neonates. Systemic cytokines produced during maternal infection and/or increases in cytokines after ischemia may accentuate damage to the fetal brain. The neurovascular unit is a privileged site that consists of brain microvascular endothelium, glia, and neurons. Although cytokines are known to cross the adult blood-brain barrier (BBB), evidence to support the hypothesis that systemic cytokines cross the BBB of the fetus and premature neonate is sparse. Our specific aims test the hypothesis that specific cytokines cross both the intact and injured BBB in the fetus to damage the brain. A consequence of this hypothesis is that blockade of these cytokines would attenuate the ischemia related damage to the neurovascular unit (BBB) and possibly the brain. A multidisciplinary approach will be used to address our hypothesis and will include physiological, biochemical, pathological, immunohistochemical, and molecular methods. Aim 1 tests the hypothesis that cytokines such as IL-1β & IL-6 cross the BBB in a maturation-dependent manner in ovine fetuses, and that maturation-related changes in barrier permeability to cytokines are primarily related to changes in the composition of the tight junction. BBB permeability will be quantified by the integral technique with α-aminoisobutyric acid and radiolabeled cytokines. Tight junction (TJ) proteins and mRNA will be measured by Western blot, immunohistochemistry, and Northern blot. Aim 2 determines whether ischemic injury increases the permeability of the BBB to cytokines as a function of gestational age and tight junction maturation. Brain ischemia is induced by carotid occlusion. BBB permeability and TJ components will be measured as in Aim 1 and brain injury assessed by pathological, immunohistochemical, and molecular methods. Aim 3 determines whether blocking the effects of cytokines with systemic infusions of neutralizing antibodies attenuates ischemic injury to the fetal neurovascular unit (BBB) and possibly the brain more in preterm than near term fetuses. IL-6 and IL-1 β blocking antibodies will be infused before ischemia. Brain ischemia will be induced and BBB permeability, TJ components, and brain injury measured as in Aim 2. These studies will provide the first direct evidence whether systemic cytokines cross the intact or injured fetal BBB and whether blocking the effects of cytokines with neutralizing antibodies protect the fetal neurovascular unit (BBB) and brain. This project may provide new insights into novel strategies to prevent brain injury in the human fetus and/or premature infant.

[2] Hormonal Regulation of Brain Maturation: The importance of the hypothalamic-pituitary-adrenocortical axis in fetal maturation is well known. Based upon findings that antenatal glucocorticoid treatment reduces blood-brain barrier (BBB) permeability early but not late in fetal development, they will continue to examine the effects of steroids on the brain in ovine fetuses, newborns and adults. The researchers use physiological, biochemical, pathological, immunohistochemical and molecular methods in our studies. These studies will test the hypothesis that endogenous steroids function as developmental regulators of the BBB via modulation of tight junction protein gene expression at the BBB in the ovine fetus. Dr. Stonestreet and her colleagues also will test the hypothesis that exogenous steroid treatment accelerates the maturation of the fetal BBB by enhancing the expression of tight junction proteins and mRNA in the BBB via a glucocorticoid receptor mediated mechanism. Expression of tight junction proteins and mRNA will be measured in brain microvessels by western and northern blot analyses after in vivo treatment of pregnant ewes, lambs and adult sheep with dexamethasone; and after in vitro exposure of brain microvessels to dexamethasone with and without exposure to RU486.

Finally, they will examine the effects of endogenous steroids via fetal adrenalectomy with and without steroid replacement, and exposure to dexamethasone, betamethasone and hydrocortisone on neurons and glia in the fetal/neonatal brain. They will test the hypotheses that endogenous steroids preserve neuronal and glial development, that precocious exposure to exogenous steroids disrupts neuronal and glia development, and that exposure to dexamethasone results in greater damage than exposure to hydrocortisone or betamethasone in the fetal/neonatal brain.

Grants and Awards

1969 Forman Fleisher Foundation Scholarship

1969 Joseph Collins Scholarship

1969 Woman's Medical College Scholarship

1970 Summer Fellowship in Neurology
Boston University

1971 Scholarship for Study Abroad
International College of Surgeons

1986 Master of Arts
Brown University

1996-1997 Listed in "The Best Doctors in America"

2003-2004 Listed in "The Best Doctors in America"

2004-2005 Listed in "Guide to America's Top Pediatricians"

2008 Listed in "Montclair Who's Who in Healthcare"

2008-2009 Listed in "The Best Doctors in America"

2009 Listed in "Marquis Who's Who in America 63rd Edition"

2011 Listed in "US News and World Reports" – Top Doctors 2011

2011 Listed in the Marquis Who's Who in America - 2011 (66th Edition).

2012 Listed in the Marquis Who's Who in America - 2012 (66th Edition).

2013 Listed in "Best Doctors in America" in 2013.

Affiliations

1970-1978 American Women's Medical Association

1978-Present American Academy of Pediatrics

1980-Present Society for Pediatric Research

1989-Present American Physiological Society

1990-Present Perinatal Research Society

1992-Present American Pediatric Society

1993-1994 New York Academy of Sciences

1997-Present Society for Neuroscience

1997-Present American Association for the Advancement of Science

2003-Present Society for Gynecological Investigation

2012-Present American Heart Association

Funded Research

Project Title: "The Effects of Asphyxia and Hypotension on
Physiologic and Anatomic Renal Parameters in the Prematurely
Delivered Lamb"
Role: Principal Investigator
Funding Agency: Charles H. Hood Foundation for Child Health
Duration of Award: 1979-1982
Amount per Year: $24,500

Project Title: "The Effects of Asphyxia and Hypotension on
Renal Physiology and Anatomy in Preterm and Term Lambs"
Role: Principal Investigator
Funding Agency: Basil O'Connor Starter Research, The National
Foundation, March of Dimes, No. 5-256
Duration of Award: 1982-1983
Amount per Year: $64,790

Project Title: "Circulatory Alterations in the Neonatal Brain"
Role: Principal Investigator
Funding Agency: American Heart Association Grant-In-Aid
Duration of Award: 1982-1983
Amount per Year: $10,086

Project Title: "Diabetes during Pregnancy: Effects on the Offspring.
Fetal Circulatory Adjustments in the Diabetic Pregnancy" (Sub-project VIII)
Role: Principal Investigator
Funding Agency: NICHDP50 11343
Duration of Award: 1985-1990
Amount per Year: $46,717

Project Title: "Diabetes during Pregnancy: Effects on the Offspring.
Fetal Circulatory Adjustments in the Diabetic Pregnancy" (Sub-project VIII)
Role: Principal Investigator
Funding Agency: NICHDP50 11343
Duration of Award: 1990-1992
Amount per Year: $352,146

Project Title: "Metabolism in the Ovine Fetus" (Sub-contract from
L. Levitsky, M.D.)
Role: CO-Investigator
Funding Agency: NICHHD HD22891
Duration of Award: 1990-1991
Amount per Year: $40,000

Project Title: "Evaluation of Three Dosing Procedures for the
Administration of Survanta7 (beractant) in the Treatment of
Neonatal Respiratory Distress Syndrome"
Role: Principal Investigator
Funding Agency: Ross Laboratories
Duration of Award: 1991
Amount per Year: $40,000



Project Title: "Multicenter Neonatal Network"
Role: CO-Principal Investigator
Funding Agency: NIH
Duration of Award: 1991-1992
Amount per Year: -

Project Title: "Diabetes during Pregnancy: Effects on the Offspring.
Perinatal Glucose Homeostasis: Effects on the Brain" (Sub-project IV)
Role: Principal Investigator
Funding Agency: NICHDP50 HD11343
Duration of Award: 1991-1995
Amount per Year: $148,934

Project Title: "Effect of Antenatal Steroid Therapy on Hemodynamic
Adaptation to Birth"
Role: CO-Principal Investigator
Funding Agency: Wyeth Pediatric Neonatology Research Fund
Duration of Award: 1995-1996
Amount per Year: $3,400

Project Title: "Effects of Monophosphoryl Lipid R on Intestinal
Ischemia/Reperfusion in Newborn Piglets"
Role: Principal Investigator
Funding Agency: RIBI Immunochemical
Duration of Award: 1996-1997
Amount per Year: $45,000

Project Title: "Hormonal Regulation of Brain Maturation"
Role: Principal Investigator
Funding Agency: NIH 1RO1-HD/NS 3461801A1
Duration of Award: 1997-2001
Amount per Year: $152,002

Project Title: "Cytokines and the blood-brain barrier in the ovine fetus"
Role: Principal Investigator
Funding Agency: NIH R01HD057100-01
Duration of Award: 2008-2013
Amount per year: $204,961.00

Project Title: Neuroprotective anti-Inflammatory strategies to prevent damage to the premature brain
Role: Principal Investigator
Funding Agency: Rhode Island Research Alliance Collaborative Grant Awards
Project Number: RIRA 2010-42
Duration of Award: 2/1/2010 – 06/30/2011
Amount per Year: $199,953

Project Title: Cytokines and the blood-brain barrier in the ovine fetus - Stimulus supplement for Stereo Investigator Software and Microscope
Role: Principal Investigator
Funding Agency: NIH
Project Number: 3R01HD057100-03S1
Duration of Award: 10/1/2009-9/30/2010
Amount per Year: $95,000

Project Title: Anti-inflammatory intervention and neurobehavioral outcome in neonatal ischemia
Role: Co-PI Mentor
Funding Agency: National Institutes of Health (NIH) RI-INBRE Program
Project Number: P20RR016457-11
Duration of Award: 5/1/2011 - 4/30/2013
Amount per year: $45,000

Project title: Anti-inflammatory interventions to attenuate ischemic brain damage in fetal sheep.
Role: Co-PI/Mentor
Funding Agency: 2011-2012 Klaus Perinatal Research Award
Duration of Award: 1 year
Amount per year: $5000.00

Project Title: Effects of IL-1β on tight junction proteins of the blood-brain barrier and potential attenuation by anti-IL-1b neutralizing antibodies
Role: Mentor
Funding Agency: Received the 2012 Summer Assistantship through Brown University's Basic and Translational Research (BTR) Program training grant from the National Heart, Lung and Blood Institution, NIH
Project # T35 HL094308
Duration of Award: 2011-2012
Amount per year: $4370.00

Project Title: Neonatal Brain Injury: Mediating Factors for Improved neurobehavioral Outcome
Role: Mentor-Consultant
Funding Agency: National Institute of Health
Project# R15HD077544
Duration of Award: 07/01/2013-06/30/2015
Amount per year: $125,000

Project title: The Neuroprotective effects of New Anti-HMGB1 Antibodies in Neonatal Hypoxic-Ischemic Brain Injury
Role: Mentor
Funding Agency: American Heart Association
Project #13POST1680015
Duraiton of Award: 07/01/2013-06/30/2015
Amount per year: $89,000

Selected Publications

  • Malaeb, S.N., Sadowska, G. B., and Stonestreet, B.S. Effects of maternal treatment with corticosteroids on tight junction protein expression in the ovine fetal cerebral cortex with and without exposure to in-utero brain ischemia. Brain Res. 1160C: 11-19, 2007. (2007)
  • Stonestreet, B.S., Sadowska, G.B., Leeman, J., Hanumara, R.C., Petersson, K.H., Patlak, C.S. Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs. Am J Physiol. Regul. Integr. Comp. Physiol. 18 (4): 413-423, 2006. (2006)
  • Sadowska, G. B., Patlak, C.S., Petersson, K.H., Stonestreet, B.S. Effects of multiple courses of antenatal corticosteroids on blood-brain barrier permeability in the ovine fetus. J. Soc. Gynecol. Investig. 13 (4): 248-255, 2006. (2006)
  • Kim, CR., Sadowska, G.B., Petersson, K.H., Merino, M., Sysyn, G.D., Padbury, J.F., and Stonestreet, B.S. Effects of postnatal steroids on Na+, K+-ATPase activity and α1- and β1-subunit protein expression in the cerebral cortex and renal cortes of newborn lambs. Reprod. Fert. Dev. 18 (4): 413-423, 2006. (2006)
  • Gray, S., Stonestreet, B.S., Thamotharan, S., Sadowska, G.B., Daood, M., Watchko, J., and Devaskar, S.U. Skeletal muscle glucose transporter protein responses to antenatal glucocorticoids in the ovine fetus. J. Endocrinol. 189: 219-229, 2006. (2006)
  • Pua, Z.J., Stonestreet, B.S., Cullen, A., Shahsafaei, A., Sadowska, G.B., and Sunday, M.E. Histochemical analyses of altered fetal lung development following single vs multiple courses of antenatal steroids. J. Histochem. Cytochem. 53 (12): 1469-1479, 2005. (2005)
  • Ron, N.P., Kazianis, J.A., Padbury, J.F., Brown, C.M., McGonnigal, B.G., Sysyn, G.S., Sadowska, G.B., Stonestreet, B.S. Ontogeny and the effects of corticosteroid pretreatment on aquaporin water channels in the ovine cerebral cortex. Reprod. Fertil. Dev. 17(5): 535-542, 2005. (2005)