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Mechanism of Perinatal Brain Injury

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Mechanism of Perinatal Brain Injury Sponsored Lecture 1 Mechanism of perinatal brain injury Henrik Hagberg Perinatal Center, Sahlgrenska Academy, Gothenburg, Sweden Centre for the Developing Brain, King’s College London, London, United Kingdom Mitochondria are dynamic double-membrane-bound organelles that are involved in a wide range of cellular processes, including ATP generation, calcium homeostasis, as well as the biosynthesis of amino acids, lipids and nucleotides. They differ with respect to size, density, ROS production, respiratory/Ca2+ regulatory activity and substrate preference in the immature compared with adult brain, suggesting unique control mechanisms in the developing CNS. Mitochondria are center stage in the regulation of cell death in the immature brain. They control apoptotic, necrotic/necroptotic and autophagic events after injury and their dynamic properties seems critical for CNS development and maybe also cell fate. Mitochondrial biogenesis, mitophagy and transcellular exchange can be important for repair processes in several tissues including the CNS. Mitochondria are also, at least partly, responsible for induction of CNS tolerance in the immature brain. Mitochondria have recently been recognized as an important scaffold for innate immune responses related to pattern recognition receptor regulation. We propose that mitochondria are important in both anti-microbial defense as well as triggering of infl ammation after sterile insults. Based on this knowledge, mitochondria-directed neuroprotective therapies (“Mitoprotectants”) such as caspase-2 inhibitors are being developed to combat injurious events in the immature brain. We found recently that magnesium (Mg) in therapeutic concentrations given as a bolus dose 12h-3days prior to hypoxia-ischemia (HI) provides marked preconditioning protection. This effects is different compared with hypoxic preconditioning as it is unrelated to cerebral blood fl ow during the subsequent HI. We hypothesize that Mg induces mitoprotection through regulation of mitochondrial Ca2+ fl uxes, mitochondrial ATP-sensitive K + channels and transient receptor potential ion channels. It is reasonable to believe that further insights into these basic and pathological aspects of mitochondria will be of paramount importance for understanding brain development, neurologic disease and for fi nding new strategies for treatment. CURRICULUM VITAE Henrik Hagberg Born: March 31, 1955, Stockholm, Sweden, two children Professional preparation 1979-1985 Medicine doktor, (PhD) Thesis: “Electrolyte, pH and metabolic changes in skeletal muscle during ischemia” Supervisor: Hengo Haljamäe, PhD, Dept of Neurobiology, Göteborg, Sweden 1987 Registered Physician (Legitimerad läkare) 1976-1985 Läkarexamen (MD), Sahlgrenska Academy, Göteborg, Sweden Appointments 2012-09 - Professor in Perinatology and Obstetrics, Department of Clinical Sciences, Department of Obstetrics and Gynecology, Sahlgrenska Academy, Göteborg and Professor, Chair in Fetal Medicine, Centre for the Developing Brain, Perinatal Imaging & Health, Kings College London, London 2010-2012-08 Shared Professorship in Perinatology and Obstetrics, Department of Clinical Sciences, Department of Obstetrics and Gynecology, Sahlgrenska Academy, Göteborg and Imperial College, Institute of Reproductive and Developmental Biology, London. 2008-2010 Professor in Obstetrics, Imperial College, Institute of Reproductive and Developmental Biology, Queen Charlotte’s and Chelsea Hospital, London 2000-2008 Professor in Perinatal Medicine and Obstetrics, Institute for the Health of Women and Children, Sahlgrenska Academy, Göteborg University 2000-2001 Guest professor at the Neuroscience Lab, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, USA 1995-1999 Associate Professor and senior clinical consultant in Perinatal Medicine and Obstetrics 1993-1995 Assistant Professor (Docent) in Obstetrics and Gynecology, Göteborg and consultant physician at the Dept of Obstetrics and Gynecology, Sahlgrenska University Hospital 1985- Assistant Professorship (Docent) in Neurobiology 1994-1998 Research assistant, Swedish Medical Reasearch Council 1997 Associate Professor, (“Docentur”; Experimental Medicine) 1991-1993 Consultant in Obstetrics and Gynecology, Göteborg 1987-1991 Residency, Borås hospital, Mölndals hospital and Sahlgrenska University Hospital 1985-1987 Internship (AT-tjänstgöring), Mölndals hospital, Mölndal Commissions of trust Abstracts for The 46th International Congress on Pathophysiology of Pregnancy 39 Commissioned to be opponent at 16 occasions for the following Ph.D. examinations: Hiroaki Minamisawa, (Lund, 1995); Ping-An Li, (Lund 1996); Lars Gisselsson, (Lund1998); Kersti Haaland, (1999,Oslo); Gregor Tomasevic, (Lund 1999); Cacha Peeters-Scholte, (Utrecht 1999); Jhodie Duncan, (Melbourne, AUS, 2000); Kristina Thorngren-Jerneck, (Lund 2002); Stefan Kutzsche, (Oslo 2002); Bhatia Inderjeet, (Hong Kong 2003); Evylin van den Tweel, (Utrecht 2004); Nasim Farrokhina (Uppsala 2005); Charlotte Israelsson (Uppsala 2006); Eva Wiberg-Itzel, (Stockholm 2007); Barbara Botallico, (Lund 2007); Elisabeth Fröyland, (Oslo 2008) External Examiner, VIVA, UCL, PhD Giles Kendall, 5/10/2009; Internal Examiner, VIVA, ICL, PhD Shirin Khanjani 18/3/2010; Examiner, PhD upgrade, ICL, Lynne Sykes, 2/3/2010; Assessment of PhD proposal, ICL, Lynne Sykes, 26/11/2008; Co-examiner VIVA, MSc, Caroline Copeland, 9/3/2009; Opponent ( = external examiner) disputation ( = VIVA) in Lund University, Sweden, Ph D Tina Markus 30/5/2009 Awards ■ Young scientist award of 1990 at European Society for Neurochemistry (ESN) and invited to give a “Honorary lecture” at the ESN meeting in Leipzig, July 1990 ■ Recipient of The Eric Fernström Price (100.000 SEK) in Lund, Sweden, 1996 ■ Recipient of a Fullbright Scholarship for one year (2000-2001) of research at Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, USA. Host: prof M Johnston. ■ Recipient of the Lennander Award and presentation of the yearly Lennander lecture (one researcher is selected every year of all scientists in Surgical disciplines and infectious diseases in Sweden) at the Swedish Medical Society, Stockholm, Sweden, 2008 Elected member of scientific peer review committees and scientific committees ■ Reviewer of LUA grant applications in Göteborg, on behalf of the Medical Faculty 1997-present ■ Reviewer for the National Brain Foundation (“Hjärnfonden”), 1998-2003 ■ Reviewer for the National Network in Neuroscience (NNN), 1998-1999 ■ Member of the Research Committee (“Forskningsnämden” ordinarie ledamot) of the Medical Faculty, Göteborg University, Sweden, 1997-2000 ■ Member of the committee for research education (“Forskarutbildningskommittén”), 1997-2000 ■ Member of the Nominating Committee, Sahlgrenska Academy 2005-2008 ■ Reviewer for Swedish Research Council, 2011 and 2013 Networks in academia Professor M.V Johnston, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, USA [email protected] Professor A.D. Edwards, Kings College London, London, U.K., [email protected] Professor Susan Vannucci, Columbia University, New York, USA [email protected] Professor Pierre Gressens, Inserm 676, Paris, France & Kings College London, London, UK, [email protected] Entrepreneurial achievements External advisor for the neuroprotection drug development at Cerebrovascular Disorders, Hoechst AG, 1987-1995 Member of the international advisory board at Neurophyxia (development of brain protective drugs for newborns) October 2003-2009 Invitations/ specific tasks Invited speaker at 186 international meetings and 12 national scientific meetings 1988-2013. Previous PhD-students: 30 PhD-students Peter Andiné, 1992, Consultant in Psychiatry; Klas Ostwald, 1994, Assistant Professor; Bo Sultan, 1994, Director of Ob/Gyn in Älvängen, Norway; Mats Blennow, 1995, Head in Neonatology Karolinska Institute, Assistant Professor; Ralph Bågenholm, 1995, Consultant in Neurology; Elsa Bona, 1997, Consultant in Pediatrics; Eric Gilland, 1997, Consultant in Neurology; Ulla-Britt Wennerholm, 1998, Assistant Professor and Consultant in Obstetrics and Gynecology; M Puka-Sundvall, 2000, Teacher of Natural Sciences; Camilla Revesjö, 2000, Bachelor of Medicine; Karin Sävman, 2001, Consultant in Neonatology; Ellen Samuelsson, 2002, Research Midwife; Bo Jacobsson, 2003, Consultant in Obstetrics and Research fellow; Lena Mårtensson, 2003, Head at Skövde University; Ulrika Hallin, 2004, Bachelor of Medicine Xiaoyang Wang, 2004, Research fellow and consultant in Pediatrics; Maj Hedtjärn, 2004, Research Fellow; Katarina Brywe, 2004, Consultant in Obstetrics; Saskia Eklind, 2004, Consultant in Gynecology; Changlian Zhu, 2004, Research fellow and Head of Neonatology; Anna-Karin Welin, 2005, Consultant in Obstetrics; Malin Gustavsson, 2005, Research assistant; Margareta Mollberg, 2007, Senior lecturer: Helen Elden, 2008, Senior lecturer; Pernilla Svedin, 2008, Research assistant; Håkan Norén, 2008, Consultant in Obstetrics and Gynecology, Rose-Marie Holst, 2009, Consultant in Obstetrics and Gynecology; Christina Doverhag, 2010, Research assistant; Katarina Järlestedt, 2010, Research assistant; Ylva Carlsson, 2011, Consultant in Obstetrics. Other Qualification Funding 3.0 MSEK/year including grants from the Swedish Research Council, EU and ALF; UK MRC award 2008-2011 1 M UK pounds, Leducq Foundation 1 MSD/year 2011-2016, Wellcome Trust 2010-2015 1,1 M UK pounds, Sparks 150k GBP 2013-2015. Research publications: 256 original articles, 2 manuscripts
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