PHA/AHA Post Doctoral Fellowship Award Winner 2004

Georg Hansmann, M.D., Ph.D.Georg Hansmann, M.D., Ph.D.

Stanford University School of Medicine, CA
Sponsor: Marlene Rabinovitch, M.D.
"Bone Morphogenetic Protein Receptor Mediated Gene Regulation in the Pathobiology of Pulmonary Hypertension"
Term: July 1, 2004 - June 30, 2006

Currently: Physician Scientist/Clinical Fellow in the Department of Cardiology, Children's Hospital Boston, Harvard Medical School

Summary of Research Project:

Bone Morphogenetic Protein Receptor Mediated Gene Regulation in the Pathobiology of Pulmonary Hypertension

Published Research Hansmann Circulation 2007 (PDF)
Published Research Hansmann JCI 2008 (PDF)
Published Research Hansmann ERJ 2009 (PDF)

Dr. Rabinovitch’s group has shown that the release of the transcription factor, AML1, from the nuclear matrix to the nuclear extract, is associated with increased elastase activity (Mitani Y et al. FASEB J 2001), a key event in the development of pulmonary vascular disease (Cowan K et al. Nature Medicine 2000). Work related to my PHA research proposal was first presented at the Arteriosclerosis Thrombosis Vascular Biology (ATVB) 6th Annual Conference in Washington, DC in April 2005. This was a platform session in which we showed the opposing effects of bone morphogenetic protein (BMP) and epidermal growth factor (EGF) in regulating transcriptionally active AML1 in human pulmonary artery smooth muscle cells (SMC): BMP-2 shuttles AML1 from the nuclear extract to the nuclear matrix where it is either non-transcriptionally active, or acts as a repressor of growth promoting genes. Loss of function mutations in the BMP-RII gene are common in idiopathic and familial forms of PAH, and our preliminary results suggest that this would lead to enhanced growth-promotive activity of AML1. This research project is still in progress: We are especially interested in the cross-talk between AML1, SMAD1, peroxisome proliferator-activated receptor gamma (PPARgamma) and wingless (Wnt) and related signaling downstream of BMP receptor II (BMP-RII).

Moreover, we have performed molecular and cell biology studies in which I first constructed a small hairpin RNAi pLentivirus to stably knock-down BMP-RII in human pulmonary artery smooth muscle cells (HPASMC). This receptor is mutated in pulmonary arterial hypertension leading to abnormal vascular cell proliferation and migration. I have since shown in HPASMC that BMP-2 signals through BMP-RII, and further demonstrated that there is rapid nuclear translocation and DNA binding of PPARgamma in response to BMP-2 stimulation. This is important because PPARgamma suppresses smooth muscle cell proliferation and BMP-2 signals through BMP-RII. We are currently investigating whether loss of PPARgamma activity directly leads to disturbed gene regulation downstream of BMP-RII signaling in the pulmonary circulation (for PASMC: see Journal of Clinical Investigation 2008; 118: 1846-1857).

We also carried out whole animal studies in apoE deficient mice (apoE -/-) and thereby established a novel mouse model for pulmonary arterial hypertension (PAH) associated with insulin resistance. Strikingly, oral treatment with an insulin-sensitizing PPARgamma agonist led to complete regression of PAH (i.e. regression of increased right ventricular systolic pressure as an indicator of PA pressure, right ventricular hypertrophy and peripheral pulmonary arterial muscularization) in insulin-resistant apoE -/- mice (see Circulation 2007; 115: 1275-1284). In collaboration with Dr. Roham T. Zamanian and colleagues, we then demonstrated that insulin resistance is more prevalent in 81 women with PAH (mean age 49.1±19.3 yrs) than in the general population, and may be a novel risk factor or disease modifier that might impact on survival (European Respiratory Journal 2009; 33: 318-324 epub 12/2008). Taken together, we suggest that PPARgamma agonists might reverse SMC proliferation and vascular remodeling in insulin-sensitive and insulin-resistant PAH patients with or without BMP-RII dysfunction. 

Curriculum Vitae

Medical School

1992-1999 Albert-Ludwigs-University, Freiburg, Germany

Thesis

1995-1999 "Characterization of P2 receptors mediating endothelium-dependent relaxation of rat aorta and human coronary artery". Department of Pharmacology, Albert-Ludwigs-University, Freiburg, Germany.

Residency / Clinical Fellowships / Postdoctoral Research Fellowships

  • 2000-2001 Department of Medicine, Division of Cardiology, Charité, Humboldt University (Resident) and Max Delbrück Center for Molecular Medicine (PostDoc), Berlin, Germany
  • 2001-2002 Department of Pediatric Cardiology, German Heart Center and Technical University of Munich, Germany (Resident/Clinical Fellow): Cardiac Intensive Care Unit, Neonatal Intensive Care Unit & Neonatal Emergency Transport Service, Pediatric Anesthesiology
  • 2003-2004 Departments of Neonatology (Clinical Fellow), General Pediatrics and Hematology&Oncology: Neonatal Intensive Care Unit, Neonatal Emergency Transport Service, Hematology& Oncology, Emergency Room, Otto-Heubner-Center for Pediatrics and Adolescent Medicine, Charité Campus Virchow Hospital, Humboldt University, Berlin, Germany
  • 2004-2006 Postdoctoral Research Fellowship (AHA/PHA grant 0425943H), Vera Moulton Wall Center for Pulmonary Vascular Disease (Research Director: Dr. Marlene Rabinovitch), Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, California, USA
  • 2006-2008 Department of Pediatrics (Physician Scientist/R2-3), University of California San Francisco, USA
  • 2008-present Department of Cardiology, Children’s Hospital Boston, Harvard Medical School, Massachusetts, USA

Medical Licensing and Board Certifications

  • 1999 Medical License, Land Baden-Württemberg, Germany
  • 1999-2006 United States Medical Licensing Examination (USMLE / ECFMG): USMLE steps 1, 2 and 3, TOEFL, CSA (and renewal 06/2005 as USMLE step 2 CS)
  • 2008 Full License (Physician and Surgeon), Medical Board of California
  • 2008 Full License (Physician and Surgeon), Board of Registration in Medicine, Massachusetts
  • 2008 Board certification in Pediatrics, Medical Board, Berlin, Germany
  • 2008 Board certification in Pediatrics (Diplomate), American Board of Pediatrics (AAP)
  • 2008 Board certification in Neonatology, Medical Board, Berlin, Germany

Honors

  • 1998 DFA grant (6th year attachment, Surgery, Cape Town, South Africa)
  • 1999 Albrecht Fleckenstein Prize, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
  • 1999 Thesis “summa cum laude”, Albert-Ludwigs-University, Freiburg, Germany
  • 2004 Postdoctoral Research Fellowship Award, Pulmonary Hypertension Association (PHA) / American Heart Association (AHA)
  • 2005 Junior Investigator Travel Stipend Award, Council on Cardiopulmonary, Perioperative & Critical Care (CPCC), American Heart Association
  • 2006 Cournand & Comroe Young Investigator Prize, Council on Cardiopulmonary, Perioperative & Critical Care (CPCC), American Heart Association
  • 2007 Best Poster Award, 1st International Conference on Childhood Pulmonary Vascular Disease, San Francisco
  • 2007 Cayman Travel Grant
  • 2007 DIVI Research Stipend, German Interdisciplinary Association of Critical Care Medicine (DIVI)
  • 2008 SPR Research Award, Society for Pediatric Research
  • 2009 Keystone Symposia Scholarship (NIH)

Memberships

  • 2003-… German Society for Perinatal Medicine (DGPM)
  • 2003-… Society for Neonatology and Pediatric Intensive Care (GNPI), Germany
  • 2004-… American Heart Association (AHA)
  • 2004-… Council on Cardiopulmonary, Perioperative & Critical Care, AHA
  • 2004-… Pulmonary Hypertension Association (PHA), USA
  • 2004-… German Society for Pediatrics and Adolescent Medicine (DGKJ)
  • 2005-… European Resuscitation Council (ERC)
  • 2006-… Interdisc. Working Group on Functional Genomics & Translational Biology, AHA
  • 2006-… American Thoracic Society (ATS)
  • 2006-… American Academy of Pediatrics (AAP)
  • 2006-… Stanford Cardiovascular Institute, Stanford University, California
  • 2007-… European Respiratory Society (ERS)
  • 2008- Leadership Committee, Council on Cardiopulmonary, Perioperative, and Critical Care (CPCC), American Heart Association
  • 2009-… Pulmonary Vascular Research Institute (PVRI)

Published Articles

  • Bültmann R, Hansmann G, Tuluc F, Starke K (1997) Vasoconstrictor and vasodilator effects of guanine nucleotides in the rat aorta. Naunyn-Schmiedeberg's Archives of Pharmacology 356: 653- 661
  • Hansmann G, Bültmann R, Tuluc F, Starke K (1997) Characterization by antagonists of P2- receptors mediating endothelium-dependent relaxation in the rat aorta. Naunyn-Schmiedeberg's Archives of Pharmacology 356: 641-652
  • Hansmann G, Ihling C, Pieske B, Bültmann R (1998) Nucleotide-evoked relaxation of human coronary artery. European Journal of Pharmacology 359: 59-67
  • Hauck L, Hansmann G, Dietz R, von Harsdorf R (2002) Inhibition of hypoxia-induced apoptosis by modulation of retinoblastoma protein-dependent signaling in cardiomyocytes. Circulation Research 91: 782-789
  • Hansmann G (2004) Neonatal resuscitation on air: it is time to turn down the oxygen tanks. Lancet 364: 1293-1294 (correction Lancet 2005; 365: 386)
  • Hansmann G, Wagner RA, Schellong S, de Jesus Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M (2007) Pulmonary arterial hypertension is linked to insulin resistance and reversed by PPARgamma activation. Circulation 115: 1275-1284
  • Gunn AJ, Hoehn T, Hansmann G, Bührer C, Simbruner G, Yager J, Levene J, Hamrick SEG, Shankaran S, Thoresen M (2008). Hypothermia: an evolving treatment for neonatal hypoxic ischemic encephalopathy. Pediatrics 121: 648-649
  • Hoehn T, Hansmann G, Bührer C, Simbruner G, Gunn AJ, Yager J, Levene M, Hamrick SEG, Shankaran S, Thoresen M (2008). Therapeutic hypothermia in neonates. Resuscitation 78: 7-12
  • Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekkers J, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M (2008). An antiproliferative BMP-2/PPARgamma/ApoE axis in human and murine smooth muscle cells and its role in pulmonary hypertension. Journal of Clinical Investigation 118: 1846-1857
  • Zamanian RT*, Hansmann G*, Snook S, Lilienfeld D, Rappaport K, Rabinovitch M, Reaven G, Doyle RL (2009). Insulin Resistance and Pulmonary Arterial Hypertension. *Both authors contributed equally to this work. European Respiratory Journal 33: 318-324 epub December 1, 2008
  • De Felice C, Bechelli S, Tonni G, Latini G, Hansmann G (2009). Systematic underestimation of oxygen delivery in ventilated preterm infants. Neonatology in press
  • Guignabert C, Alvira CM, Alastalo TP, Sawada H, Hansmann G, Zhao M, Wang L, El-Bizri N, Rabinovitch M (2009). Tie2-mediated loss of peroxisome proliferator-activated receptor-g in mice causes PDGF-receptor β-dependent pulmonary arterial muscularization. American Journal of Physiology – Lung Cellular and Molecular Physiology 2009 in press

Review articles

  • Hansmann G, Humpl T, Zimmermann (2004) Neonatal Emergencies: basics in cardiopulmonary resuscitation [German]. Z Geburtshilfe Neonatol 208: 43-56
  • Hansmann G, Humpl T, Zimmermann A, Bührer C, Stannigel H, Hoehn T (2007). ILCOR’s new resuscitation guidelines in preterm and term infants: critical discussion and suggestions for implementation [German]. Klin Päd 219: 50-57 national guidelines
  • Hansmann G, Bührer C, Dzietko M, Höhn T (2007) Initial care and resuscitation of newborn infants [German]. Notfallmedizin up2date 2: 21-42 invited review
  • Hoehn T, Humpl T, Zimmermann A, Hansmann G (2007) New resuscitation guidelines and specific emergencies in preterm and term newborn infants [German]. Notfall- und Rettungsmedizin 10: 82-93 invited review
  • Hoehn T, Humpl T, Zimmermann A, Dzietko M, Nicolai T, Hansmann G (2008). Special emergencies in preterm and term infants [German]. Monatsschrift Kinderheilkunde 156: 489–504

Case Reports

  • Hansmann G, Haas F, Sadiq M, Brook M, Gildein HP (2009). Arrival and survival of a 3 week old boy from Pakistan with an arterial oxygen saturation of 17%. British Medical Journal in press

Books

  • Hansmann G (1999) Characterization of endothelial, relaxation-mediating P2 receptors in rat aorta and human coronary artery [German]. Tectum Verlag Marburg, 99pp.
  • Hansmann G (ed.), Humpl T, Zimmermann A (2004) Neugeborenen-Notfälle [Neonatal Emergencies]. Thieme Stuttgart New York, 463pp. ISBN-13: 978-3131358912
  • Hansmann G (ed.). Contributions by Arnold JH, Buehrer C, Fenton AC, Hamrick SEG, Hansmann G, Humpl T, Ibla J, Richmond S, Zimmermann A (2009) Neonatal Emergencies. Cambridge University Press Cambridge New York, approx. 550pp., in press. ISBN-13: 978-0521701433

Papers and Abstracts (PDF)

 

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