Research Funding
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
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)
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 abstracts and Circulation 2007; 115: 1275-1284).
Taken together, we therefore 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.
MEDICAL SCHOOL, POSITIONS, MEMBERSHIPS AND HONORS
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.
Medical Licensing Examination (USMLE / ECFMG)
1999-2006 USMLE steps 1, 2 and 3, TOEFL, CSA (renewal 06/2005: USMLE step 2 CS)
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
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 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
Memberships
- 2003-… German Society for Perinatal Medicine (DGPM)
- 2003-… Society for Neonatology and Pediatric Intensive Care (GNPI), Germany
- 2004-… Council on Cardiopulmonary, Perioperative & Critical Care, AHA
- 2004-… American Heart Association (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, American Heart Association
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 Investigation118: 1846-1857
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
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.
- Hansmann G (ed.). Contributions by Arnold JH, Buehrer C, Fenton AC, Hamrick SEG, Hansmann G, Humpl T, Ibla J, Richmond S, Zimmermann A (2008) Neonatal Emergencies. Cambridge University Press Cambridge New York, approx. 500pp., estimated publication 12/2008
