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Jesse David Roberts Jr., M.D.

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Biography
1982
William Boger Award for Research
1985 - 1987
National Research Service Award
1997 - 2009
Society for Pediatric Research
2000 - 2004
Mentored Clincal Scientist Award
2005
Memorial Metal
2009
American Pediatric Society, elected

Overview
Lung injury in children often causes abnormal pulmonary arterial vasoreactivity and muscularization. Through processes that are incompletely understood, many children with lung injury develop progressive and irreversible pulmonary hypertension, intra- and extra-pulmonary shunting of deoxygenated blood, and severe hypoxemia. The long-term goals of my laboratory are to explore the fundamental mechanisms of lung injury and to develop novel therapies for pulmonary vascular disease.

We have discovered that inhaled nitric oxide (NO) gas modulates pulmonary vasoconstriction associated with pulmonary vascular disease. In the lung, NO is produced by endothelial cells diffuses into subjacent smooth muscle cells (SMC), where it increases cGMP levels and causes vasorelaxation. Because endogenous NO-cGMP signaling is decreased in patients with pulmonary vascular disease, we tested whether or not exogenous NO decreases pulmonary hypertension. In newborn lambs with pulmonary hypertension, we observed that low levels of inhaled NO rapidly cause pulmonary vasodilatation. Furthermore, the dilator effect of inhaled NO was limited to the lungs since it did not cause systemic vasodilatation. After evaluating the dose-response to inhaled NO in the laboratory and developing a safe NO delivery system, we performed the first clinical trials of inhaled NO in pediatric patients with pulmonary hypertension. Low levels of inhaled NO were observed to safely decrease hypoxemia and pulmonary hypertension in critically ill newborns with pulmonary vascular disease and intrapulmonary shunt. Subsequently, I lead a prospective, randomized, placebo controlled, multicenter study that demonstrated that inhaled NO treatment decreases hypoxemia and the requirement for extracorporeal membrane oxygenation (ECMO) in newborns with pulmonary hypertension. These studies stimulated investigations of inhaled NO in the pediatric lung through out the world and were pivotal in the acceptance of inhaled NO by the Federal Drug Administration of the United States as a therapy for pulmonary hypertension and hypoxemia in newborns. We also were the first to perform studies examining whether or not inhaled NO ameliorates pulmonary hypertension in patients with structural heart lesions. In the cardiac catheterization laboratory, we demonstrated that inhaled NO safely and selectively decreases pulmonary vasoconstriction in infants and children with congenital heart disease and pulmonary hypertension. These later observations were the basis for several clinical trials that were performed demonstrating that inhaled NO prevents malignant pulmonary hypertension in many pediatric patients following cardiac surgery.

Our investigations also revealed that inhaled NO prevents abnormal pulmonary vascular remodeling in the injured lung. Previous studies indicate that NO signaling regulates cell proliferation. Our previous studies indicated inhalation NO is selectively delivered to the lung and has minimal systemic effects. Therefore, we tested whether or not inhaled NO decreases pulmonary artery cell proliferation in newborn animals with lung injury. We observed that inhaled NO attenuates abnormal pulmonary artery remodeling in newborn animals. Furthermore, we determined that inhaled NO protects the lung against abnormal remodeling by directly inhibiting the proliferation of pulmonary artery smooth muscle cell precursors. These fundamental discoveries have recently stimulated the formation of several clinical investigations that are testing whether or not inhaled NO prevents pulmonary vascular disease in newborns with lung injury.

Our recent studies indicate that NO regulates vascular smooth muscle cell proliferation through the activation of cGMP-dependent protein kinase (PKG). The antiproliferative mechanisms of NO are incompletely understood. Studies suggest that NO directly decreases the proliferation of cultured cells. However, NO has been observed to nonspecifically nitrosylate proteins and DNA. Therefore, it is possible that the direct antiproliferative effect of NO observed in vitro is nonphysiologic. In smooth muscle cells, NO increases cGMP by stimulating soluble guanylate cyclase. Through this second messenger, NO has been observed to stimulate PKG activity. We hypothesized that the antiproliferative effect of NO in smooth muscle cells is through the modulation of PKG activity. However, to test this mechanism in vitro is difficult since cultured vascular smooth muscle cells do not express PKG. Therefore, we first constructed an adenovirus that encodes an inducible isoform of human PKG and demonstrated that it causes the expression of PKG in infected, cultured smooth muscle cells that is the same as what is observed in arteries and in freshly dispersed pulmonary artery cells. We then demonstrated that stimulation of PKG in these cells inhibits their proliferation. Additionally, the stimulation of PKG was observed to completely account for the antiproliferative effect of NO. These investigations demonstrate that NO-PKG signaling importantly regulates vascular smooth muscle cell proliferation . Furthermore, they indicate that the investigation of PKG phosphoryation targets may be important in the development of novel therapies that prevent the abnormal smooth muscle cell proliferation observed in pulmonary vascular disease.

In summary, our studies reveal that inhaled NO is an important therapy for pulmonary vascular disease in newborns and children. Additionally, NO-PKG signaling is an important antiproliferative mechanism in vascular smooth muscle cells.

Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. R01HL125715 (ROBERTS, JESSE D) Sep 1, 2015 - Jun 30, 2019
    NIH/NHLBI
    TGFB and Nitric Oxide Signaling in Pediatric Pulmonary Vascular Disease
    Role: Principal Investigator
  2. R01HL096779 (ROBERTS, JESSE D) Apr 1, 2010 - Mar 31, 2014
    NIH/NHLBI
    Mechanisms regulating PKGI proteolysis and modulation of pulmonary SMC phenotype
    Role: Principal Investigator
  3. R01HL080316 (ROBERTS, JESSE D) May 1, 2005 - Apr 30, 2010
    NIH/NHLBI
    Mechanisms of PKG-induced PASMC Differentiation
    Role: Principal Investigator
  4. K08HL004237 (ROBERTS, JESSE D) Feb 1, 2000 - Jan 31, 2006
    NIH/NHLBI
    ANTIMITOGENIC MECHANISMS OF PKG IN VASCULAR SM CELLS
    Role: Principal Investigator

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
List All   |   Timeline
  1. Du L, Roberts JD. Transforming growth factor-beta down-regulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling. Am J Physiol Lung Cell Mol Physiol. 2018 Sep 27. PMID: 30260287.
    View in: PubMed
  2. Zhang H, Du L, Zhong Y, Flanders KC, Roberts JD. Transforming growth factor-ß stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1. Am J Physiol Lung Cell Mol Physiol. 2017 Sep 01; 313(3):L615-L627. PMID: 28642261.
    View in: PubMed
  3. Kato S, Chen J, Cornog KH, Zhang H, Roberts JD. The Golgi apparatus regulates cGMP-dependent protein kinase I compartmentation and proteolysis. Am J Physiol Cell Physiol. 2015 Jun 01; 308(11):C944-58. PMID: 25855081; PMCID: PMC4451346.
  4. Chen J, Roberts JD. cGMP-dependent protein kinase I gamma encodes a nuclear localization signal that regulates nuclear compartmentation and function. Cell Signal. 2014 Dec; 26(12):2633-44. PMID: 25172423; PMCID: PMC4254301.
  5. Coté CJ, Sui J, Anderson TA, Bhattacharya ST, Shank ES, Tuason PM, August DA, Zibaitis A, Firth PG, Fuzaylov G, Leeman MR, Mai CL, Roberts JD. Continuous noninvasive cardiac output in children: is this the next generation of operating room monitors? Initial experience in 402 pediatric patients. Paediatr Anaesth. 2015 Feb; 25(2):150-9. PMID: 24916144.
    View in: PubMed
  6. Witsch TJ, Niess G, Sakkas E, Likhoshvay T, Becker S, Herold S, Mayer K, Vadász I, Roberts JD, Seeger W, Morty RE. Transglutaminase 2: a new player in bronchopulmonary dysplasia? Eur Respir J. 2014 Jul; 44(1):109-21. PMID: 24603819; PMCID: PMC4212268.
  7. Pieretti AC, Ahmed AM, Roberts JD, Kelleher CM. A novel in vitro model to study alveologenesis. Am J Respir Cell Mol Biol. 2014 Feb; 50(2):459-69. PMID: 24066869; PMCID: PMC3930945.
  8. Bachiller PR, Cornog KH, Kato R, Buys ES, Roberts JD. Soluble guanylate cyclase modulates alveolarization in the newborn lung. Am J Physiol Lung Cell Mol Physiol. 2013 Oct 15; 305(8):L569-81. PMID: 23934926; PMCID: PMC3798773.
  9. Kato S, Zhang R, Roberts JD. Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport. Am J Physiol Lung Cell Mol Physiol. 2013 Jul 15; 305(2):L130-40. PMID: 23686857; PMCID: PMC3726948.
  10. Witsch TJ, Turowski P, Sakkas E, Niess G, Becker S, Herold S, Mayer K, Vadász I, Roberts JD Jr, Seeger W, Morty RE. . Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia. Am J Respir Cell Mol Biol. 2013; 3(306):L246-59.
  11. Shen D, Li J, Lepore JJ, Anderson TJ, Sinha S, Lin AY, Cheng L, Cohen ED, Roberts JD, Dedhar S, Parmacek MS, Gerszten RE. Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells. Circ Res. 2011 Sep 02; 109(6):616-28. PMID: 21778429; PMCID: PMC3351207.
  12. Bachiller PR, Nakanishi H, Roberts JD. Transforming growth factor-beta modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2010 Mar; 298(3):L324-34. PMID: 20023176; PMCID: PMC2838670.
  13. Sugiura T, Nakanishi H, Roberts JD. Proteolytic processing of cGMP-dependent protein kinase I mediates nuclear cGMP signaling in vascular smooth muscle cells. Circ Res. 2008 Jul 03; 103(1):53-60. PMID: 18535260; PMCID: PMC2749497.
  14. Roberts JD, Chiche JD, Kolpa EM, Bloch DB, Bloch KD. cGMP-dependent protein kinase I interacts with TRIM39R, a novel Rpp21 domain-containing TRIM protein. Am J Physiol Lung Cell Mol Physiol. 2007 Oct; 293(4):L903-12. PMID: 17601797.
    View in: PubMed
  15. Bloch KD, Ichinose F, Roberts JD, Zapol WM. Inhaled NO as a therapeutic agent. Cardiovasc Res. 2007 Jul 15; 75(2):339-48. PMID: 17544387; PMCID: PMC1986790.
  16. Nakanishi H, Sugiura T, Streisand JB, Lonning SM, Roberts JD. TGF-beta-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung. Am J Physiol Lung Cell Mol Physiol. 2007 Jul; 293(1):L151-61. PMID: 17400601.
    View in: PubMed
  17. Heller EA, Liu E, Tager AM, Sinha S, Roberts JD, Koehn SL, Libby P, Aikawa ER, Chen JQ, Huang P, Freeman MW, Moore KJ, Luster AD, Gerszten RE. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation. 2005 Jul 26; 112(4):578-86. PMID: 16043658.
    View in: PubMed
  18. Roberts JD Jr, Kolpa E, Chiche J-D, Bloch D, Bloch K. PKG interacts with and phosphorylates novel ring finger proteins expressed in the lung. Journal of Biological Chemistry. 2005; in preparation.
  19. Nakajjima A, Yu J, Roberts JD Jr, Kieff E, Bloch KD, Bloch DB. Sp100 bridges PML- and Sp140-containing nuclear bodies; disruption of these domains by Epstein Barr virus leader protein. Journal of Biochemistry. 2005; in review.
  20. Ichinose F, Roberts JD, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004 Jun 29; 109(25):3106-11. PMID: 15226227.
    View in: PubMed
  21. Roberts JD Jr. Protective mechanisms of inhaled NO in the newborn lung. Journal of Perinatal Medicine. 2003; 31:79.
  22. Hellman J, Roberts JD, Tehan MM, Allaire JE, Warren HS. Bacterial peptidoglycan-associated lipoprotein is released into the bloodstream in gram-negative sepsis and causes inflammation and death in mice. J Biol Chem. 2002 Apr 19; 277(16):14274-80. PMID: 11830585.
    View in: PubMed
  23. Hellman J, Roberts JD Jr, Tehan MM, Allaire J, Warren HS. Bacterial peptidoglycan-associated lipoprotein circulates in septic mice and has potent inflammatory effects. Journal of Biologicl Chemistry. 2002; 277:14374-14280.
  24. Roberts JD Jr, Cromin J, Zestos MM. Anesthesia for surgical emergencies in the neonate. In: Clinical anestehsia procedures of the Massachusetts General Hospital, Hurford W, ed. 2002; 445-466.
  25. Roberts JD Jr, Cronin J, Todres JD. Neonatal emergencies. In: A practice of anesthesia for infants and children, Cote CJ, Todres ID, Goudsouzian NG, Ryan JF, eds. 2001; 294-314.
  26. Roberts JD, Chiche JD, Weimann J, Steudel W, Zapol WM, Bloch KD. Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups. Circ Res. 2000 Jul 21; 87(2):140-5. PMID: 10903998.
    View in: PubMed
  27. Roberts JD, Zapol WM. Inhaled nitric oxide. Semin Perinatol. 2000 Feb; 24(1):55-8. PMID: 10709861.
    View in: PubMed
  28. Zestos MM, Insoft R, Roberts JD Jr. Neonatal intensive care. In: Postoperative critical care procedures of the Massachusetts General Hospital, Hurfors W, ed. 2000.
  29. Lee K-H, Roberts JD Jr, Matsui T, Li L, Gianetti J, Blocj KD, Rosenzweig A. Inhated nitric oxide reduces myocardial infarct size after transient ischemia without affecting systemic hemodynamics. Circulation. 2000; 102:II-60.
  30. Catlin EA, Roberts JD Jr, Erana R, Preffer FI, Ferry JA, Kelliher AS, Atkins L, Weinstein HJ. Vertical transmission of an aggressive natural killer cell lymphoma/leukemia. The New England Journal of Medicine. 1999; 341:80-91.
  31. Chiche J-D, Schlutsmeyer SM, Bloch DB, de la Monte SM, Roberts JD Jr, Filippov G, Janssens SP, Rosenzweig A, Bloch KD. Restoration of cGMP-dependent protein kinase activity increases the sensitivity of vascular smooth muscle cells to the antiproliferative and pro-apoptotic effect of nitric oxide / cGMP. Journal of Biology Chemistry. 1998; 273:34263-34271.
  32. Zestos MM, Roberts JD Jr. Anesthesia for neonatal surgery. In: Clinical anesthesia procedures of the Massachusetts General Hospital, Hurford W, Balin MT, Davidson JK, et.al., eds. 1998; 472-498.
  33. Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997 Feb 27; 336(9):605-10. PMID: 9032045.
    View in: PubMed
  34. Roberts JD Jr. Nitric oxide and the perinatal circulation. In: Fetal and Neonatal Physiology, Polin, Fox, eds. 1997.
  35. Roberts JD Jr, Bloch KD. Alternate splicing of the vascular endothelial growth factor mRNA is modulated during lung development. Pediatric Research. 1996; 39:241A.
  36. Roberts JD Jr, Kinsella JP, Abman SH. Inhaled nitric oxide in neonatal pulmonary hypertension and severe respiratory distress syndrome: experimental and clinical studies. In: Nitric Oxide and Lung, Zapol WM, Bloch KD, eds. 1996.
  37. Lee JS, Adrie C, Jacob HJ, Roberts JD Jr, Zapol WM, Bloch KD. Chronic inhalation of nitric oxide inhibits neointimal formation after balloon arterial injury. Circulation Reserarch. 1996; 78:337-342.
  38. Bloch KD, Wolfram JR, Brown DM, Roberts JD, Zapol DG, Lepore JJ, Filippov G, Thomas JE, Jacob HJ, Bloch DB. Three members of the nitric oxide synthase II gene family (NOS2A, NOS2B, and NOS2C) colocalize to human chromosome 17. Genomics. 1995 Jun 10; 27(3):526-30. PMID: 7558036.
    View in: PubMed
  39. Roberts JD, Roberts CT, Jones RC, Zapol WM, Bloch KD. Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Circ Res. 1995 Feb; 76(2):215-22. PMID: 7834832.
    View in: PubMed
  40. Bigatello LM, Hurford WE, Kacmarek RM, Roberts JD, Zapol WM. Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation. Anesthesiology. 1994 Apr; 80(4):761-70. PMID: 8024129.
    View in: PubMed
  41. Roberts JD JR, Abman SH. Physiology of nitric oxide in the perinatal lung. In: New Therapies for neonatal respiratory failure, Boynton, ed. 1994.
  42. Stanek KS, Roberts JD Jr, Zapol WM, Falke KJ, Liggins GC, Liggins L. Thoracic circumference and nitric oxide activity in the free-diving Weddell seal. The Antarctic Journal. 1994; 29:172-174.
  43. Zayek M, Wild L, Roberts JD, Morin FC. Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension. J Pediatr. 1993 Dec; 123(6):947-52. PMID: 8229529.
    View in: PubMed
  44. Roberts JD. Inhaled nitric oxide for treatment of pulmonary artery hypertension in the newborn and infant. Crit Care Med. 1993 Sep; 21(9 Suppl):S374-6. PMID: 8365236.
    View in: PubMed
  45. Roberts JD, Chen TY, Kawai N, Wain J, Dupuy P, Shimouchi A, Bloch K, Polaner D, Zapol WM. Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res. 1993 Feb; 72(2):246-54. PMID: 8380356.
    View in: PubMed
  46. Roberts JD, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation. 1993 Feb; 87(2):447-53. PMID: 8425292.
    View in: PubMed
  47. Roberts JD Jr, Shaul P. Persistent pulmonary hypertesion of the newborn: recent advances in diagnosis and treatment. In: Pediatric Clinical North America, Hageman, ed. 1993; 983-1004.
  48. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992 Oct 03; 340(8823):818-9. PMID: 1357245.
    View in: PubMed
  49. Roberts JD Jr, Todres ID, Cote CJ. Neonatal emergencies. In: A practice of anesthesia for infants and children, Cote CJ, Ryan JF, Todres ID, Goudsouzian NG, eds. 1992; 225-246.
  50. Roberts JD Jr, Todres ID, Cote CJ. Neonatal emergencies. A practice of anesthesia for infants and children. Cote CJ, Ryan JF, Todres ID, Goudsouzian NE, eds. 1992; 225-246.
  51. Roberts JD Jr. Duodenal atresia and trisomy 21. In: Common problems in pediatric anesthesia, Stehling L, ed. 1992; 39-43.
  52. Roberts JD Jr, Todres ID. Pediatric cardiopulmonary resuscitation. In: Postoperative critical care procedures of the Massachusetts General Hospital, Hoffman W, Wasnick J, eds. 1992; 397-403.
  53. Soll RF, Hoekstra RE, Fangman JJ, Corbet AJ, Adams JM, James LS, Schulze K, Oh W, Roberts JD, Dorst JP, et al. Multicenter trial of single-dose modified bovine surfactant extract (Survanta) for prevention of respiratory distress syndrome. Ross Collaborative Surfactant Prevention Study Group. Pediatrics. 1990 Jun; 85(6):1092-102. PMID: 2187176.
    View in: PubMed
  54. Roberts JD, Oh W. Pulmonary oxygen toxicity in the guinea pig. Effect of indomethacin. Dev Pharmacol Ther. 1989; 12(2):106-12. PMID: 2714157.
    View in: PubMed
  55. Voha BR, Garcia-Coll C, Roberts JD Jr, Brown LJ, Oh W. Decreased morbidities during the first year in very low birth weight (<1200 grams) infants treated with single dose Surfactant-TA (STA) for prevention of RDS. Pediatric Research. 1989; 25:1393A.
  56. Ogburn PL Jr, Roberts JR Jr, Dassopoulos T, Walker JL. Leukotriene B$ 6-Keto-prostaglandin F1, thromboxane B2, and free arachidonic acid levels in human placental tissue. Ann. NY Acad. Sci. 1988; 524:434-435.
  57. Roberts JD Jr, Jalowayski A, Merritt TA. Reduction of cord blood polymorphonuclear (PMN) leukocyte chemotaxis by indomethacin. Pediatric Research. 1985; 19:381A.
  58. Roberts JD Jr. Pulmonary surfactant metabolism [Master's]. 1982.
  59. Roberts JD Jr, Zmora E, Merritt TA. Unidimensional TLC for resolution of amniotic fluid phospholipids. Pediatric Research. 1980; 14:609A.
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