Department of Neuroscience
Uppsala Brain Injury Center - UBIC
A Translational Approach to Traumatic Brain Injury - Molecular Mechanisms, Plasticity, Repair, Intensive Care, and Rehabilitation
Summary
UBIC is a multidisciplinary, translational research network approach to combat Traumatic Brain Injury (TBI), a major global public health problem. TBI is considered the most complex disease of the most complicated organ of the body. The UBIC network therefore consists of senior scientists with a broad spectrum of competences. The basic rational is to approach the multifactorial problems related to TBI in an integrative, collaborative strategy, reaching from molecule to man. The overall goal is to improve our understanding of the mechanisms leading to morbidity and mortality in order to identify novel targets for therapeutic intervention to improve recovery of function for TBI patients.
The following scientists are currently members of the UBIC:
Per Enblad, MD, PhD, Professor of Neurosurgery, Uppsala University
Research area: Clinical & Experimental Neurosurgery.
Lars Hillered, MDs, PhD, Professor of Neurochemistry, Uppsala University.
Research area: Experimental & Clinical Neurochemistry.
Anders Lewén, MD, PhD, Associate Professor of Neurosurgery, Uppsala University
Research area: Clinical & Experimental Neurosurgery.
Niklas Marklund, MD, PhD, Associate Professor of Neurosurgery, Uppsala University
Research area: Experimental & Clinical Neurosurgery.
Anna Erlandsson, PhD, Associate Professor of Experimental Neurosurgery, Uppsala University
Research area: Tissue regeneration and in vitro injury models.
Jörgen Borg, MD , PhD, Professor of Neurorehabilitation, Karolinska Institute
Research area: Neurorehabilitation.
Ted Ebendal, PhD, Professor of Developmental Neurobiology, Uppsala University
Research area: Molecular neuroscience.
Karin Forsberg Nilsson, PhD, Professor of Stem Cell Biology, Uppsala University
Research area: Stem cell biology.
Jöns Hilborn, PhD, Professor of Materials Chemistry, Uppsala University
Research area: Polyers for in-vivo use: Tissue engineering & drug delivery.
Klas Kullander, PhD, Associate Professor of Developmental Genetics, Uppsala University
Research area: Development and function of neuronal circuits.
Lennart Lindbom, PhD, Karolinska Institute
Research area: Microvascular research, inflammation.
Jonas Bergquist, PhD, Professor of Analytical Chemistry, Uppsala University
Research area: Neurochemistry, Proteomics, Metabolomics.
The UBIC International Advisory Board comprises leading scientists in the international field of Neurotrauma research:
Ross Bullock, MD, PhD, University of Miami
Pak H Chan, PhD, Stanford University
David A Hovda, PhD, University of California at Los Angeles
Peter Hutchinson, PhD, University of Cambridge
Lennart Persson, MD, PhD, Uppsala University
Ian Piper, PhD, University of Glasgow
John Povlishock, PhD, Medical College of Virginia
Claudia Robertson, MD, PhD, Baylor College of Medicine, Houston
Andreas Unterberg, MD, PhD, University of Heidelberg
The UBIC Steering Group
Lars Hillered, MD, PhD, (Coordinator)
Per Enblad, MD, PhD, (Clinical Neuroscience Representative)
Ted Ebendal, PhD, (Basic Neuroscience Representative)
Anders Lewén, MD, PhD, (Web Master)
Petra Millbert, (Financial Administrator)
Background
Traumatic brain injury (TBI) is a major global public health problem (U.S. Department of Health and Human Services Declaration, 1989). TBI is the leading cause of mortality and morbidity in the population below 50 years of age. Although clinical outcome of TBI victims has improved in recent years following the introduction of modern Neurointensive Care, there is still no specific pharmacological treatment available to hinder the progression of brain damage (i.e. secondary injury) triggered by the initial trauma. A number of clinical trials conducted based on promising preclinical research on neuroprotective interventions, spending huge sums of money, have failed to prove efficacy in the clinical setting. Pour target definition for intervention and insufficient translational efforts have been pointed out as major explanations for these failures. A novel concept has emerged in the international research community to tackle this problematic situation. The Neurovascular Unit (NVU) concept is intended to focus attention on the interactions among cerebral blood vessels and the cells they serve. It refers to the composite of the endothelium, extracellular matrix, astrocytes, pericytes and neurons. The term emphasizes the roles that the micro vessel and the vascular compartment play in cellular responses and the dynamics of vascular, cellular and matrix signalling in both the grey and white matter. According to the NVU concept, future studies on neuroprotection should focus on the interplay between neurons, glia, inflammatory cells and the microvasculature in acute brain injury, calling for multidisciplinary approaches.
The UBIC vision
The UBIC vision is to explore the multi-factorial problems related to TBI in an integrative, multi-disciplinary approach to achieve a better understanding of the mechanisms of TBI. The rationale is to identify new targets of therapeutic intervention that can be translated into improved Neurointensive Care and Rehabilitation, leading to improved recovery of function for TBI patients. The UBIC comprises researchers and clinicians, each with documented expertise and activity in the international forefront of their individual fields. The group has a documented ability to produce collaborative work in TBI with international recognition. The ranging from molecular work in cell cultures and animal models to neurointensive care, rehabilitation, and follow up of TBI patients is a unique feature of UBIC, both in a national and international perspective, with a potential to clarify the multi-factorial problems related to TBI. It is our conviction that this network provides excellent opportunities for defining new molecular targets for pharmaceutical intervention, new concepts of neurorepair by stem cell transplantation, improved neurointensive care, rehabilitation, and follow up of TBI patients. The UBIC members are dedicated to make a significant impact on society; by being a center of excellence producing research of top international quality and attracting young scientists; by providing new concepts for commercial exploration; and, not least, by improving health care relieving the huge suffering of TBI victims. The UBIC endeavor is of strategic relevance for strengthening the interaction between Uppsala University and the Uppsala University Hospital , and consolidating the leading role of Neurointensive Care in Sweden.
Significance of the project
This project carries great potential for providing new important insights into the secondary injury mechanisms of TBI leading to the identification of novel targets for therapeutic intervention within the areas of pharmacological neuroprotection, neurogenesis/neuroplasticity, and neurorepair by stem cell transplantation.
The translational approach involving basic and clinical scientists spans from sub cellular studies at the molecular level, to cell culture work, to studies in animal models of TBI, and to neurointensive care, rehabilitation and follow-up of human TBI patients. The over all ambition is to find new concepts of therapeutic intervention that may be added to the therapeutic arsenal in the neurointensive care setting to further improve recovery of function in human victims of TBI.UBIC Publications
- Clausen F, Lundqvist H, Ekmark S, Lewén A, Ebendal T, Hillered L (2004) Oxygen free radical dependent activation of extracellular signal-regulated kinase (ERK) mediates apoptosis-like cell death after traumatic brain injury. J Neurotrauma 21(9):1168-1182.
Frykholm P, Hillered L, Långström B, Persson L, Valtysson J, Enblad P (2005) The relation between CBF and oxygen metabolism and the extracellular glucose and lactate concentrations during middle cerebral artery occlusion and reperfusion. A microdialysis and PET study in primates. J Neurosurg 102(6):1076-84.-
Clausen F, Lewén A, Marklund N, McArthur D, Olsson Y, Hillered L (2005) Correlation of hippocampal morphology and Morris water maze performance following cortical contusion injury in rats. Neurosurgery 57(1):154-63. -
Clausen F, Hillered L (2005) Intracranial pressure changes during fluid percussion, controlled cortical impact and weight drop injury in rats. Acta Neurochir 147(7):775-80. -
Kunz T, Marklund N, Hillered L, Oliw EH (2005) Assessment of the effects of the cyclooxygenase-2 inhibitor rofecoxib on visuospatial learning and hippocampal cell death following kainate-induced seizures in the rat. Brain Res Cogn Brain Res 25(3):826-32.
Kunz T, Marklund N, Hillered L, Oliw EH (2006) Effects of the selective cyclooxygenase-2 inhibitor rofecoxib on cell death following traumatic brain injury in the rat. Restor Neurol Neurosci 24(1):55-63.
Marklund N, Salci K, Ronquist G, Hillered L (2006) Energy metabolic changes in the early post-injury period following traumatic brain injury in rats. Neurochem Res 31(8):1085-93. Epub 2006 Aug 15.-
Israelsson C, Lewén A, Kylberg A., Usoskin D, Althini S, Lindeberg J, Deng C-X, Fukuda T, Wang Y, Kaartinen V, Mishina Y, Hillered L & Ebendal T (2006). Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse. J Neurosci Res 84: 47-57.
Samuelsson C, Hillered L, Zetterling M, Hesselager G, Johansson M, Lewén A, Marklund N, Nilsson P, Salci K, Enblad P, Kumlien E, Ronne-Engstrom E (2007) Cerebral glutamine and glutamate levels in relation to compromised energy metabolism – A microdialysis study in subarachnoid hemorrhage patients. J Cereb Blood Flow Metab 27(7):1309-17 (Epub 2007 Jan 17).
Clausen F, Lorant T, Lewén A, Hillered L (2007) T-cell Trafficking - A Novel Target for Neuroprotection in Traumatic Brain Injury. J Neurotrauma 24(8):1295-307.
Brannvall K, Bergman K, Wallenquist U, Bowden T, Hilborn J, K (2007) neuronal differentiation in a three-dimensional collagen-hyaluronan matrix. J Neurosci Res 85(10):6-?.-
Israelsson C, Bengtsson H, Kylberg A, Kullander K, Lewén A, Hillered L and Ebendal T (2008) Distinct Cellular Patterns of Upregulated Chemokine Expression Supporting a Prominent Inflammatory Role in Traumatic Brain Injury J Neurotrauma 25:959-974. -
Clausen F, Marklund N, Lewén A, Hillered L (2008) The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat. J Neurotrauma 25 (12) 1449-1457. -
Marklund N, Blennow K, Zetterberg H, Ronne-Engström E, Enblad P and Hillered L (2009) Monitoring of Brain Interstitial Total Tau and β Amyloid Proteins by Microdialysis in Patients with Traumatic Brain Injury. J Neurosurg 110:1227-1237. -
Hanrieder J, Wetterhall M, Enblad P, Hillered L and Bergquist J (2009) Temporally resolved differential proteomics analysis of human ventricular CSF for monitoring traumatic brain injury biomarker candidates. J Neurosci Methods 177(2):469-78. -
Marklund N, Sihver S, Hovda DA, Långström B, Watanabe Y, Ronquist G, Bergström M and Hillered L (2009) Increased cerebral uptake of [18F]fluoro-deoxyglucose but not [1-14C]glucose early following traumatic brain injury in rats. J Neurotrauma 26:1281-1293. -
Clausen F, Hånell A, Björk M, Hillered L, Mir AK, Gram H, Marklund N (2010) Neutralization of Interleukin-1β Modifies the Inflammatory Response and Improves Histological and Cognitive Outcome Following Traumatic Brain Injury in Mice. Eur J Neurosci 30(3):385-396.
Israelsson C, Bengtsson H, Lobell A, Nilsson L, Kylberg A, Isaksson M, Wootz H, Lannfelt L, Kullander K, Hillered L and Ebendal T (2010) Appearance of Cxcl10 expressing cell clusters common for neurodegenerative disorders and traumatic brain injury. Eur J Neurosci 31:852-863.-
Wallenquist U, Brännvall K, Clausen F, Lewén A, Hillered L and Forsberg-Nilsson K (2009) Grafted neural progenitors migrate and form neurons after experimental traumatic brain injury. Restorative Neurology and Neuroscience 27(4):323-34 [IF 1.4].
Marklund N, Morales D, Clausen F, Hånell A, Kiwanuka O, Pitkanen A, Gimbel DA, Philipson O, Lannfelt L, Hillered L, Strittmatter SM, McIntosh TK (2009) Functional outcome is impared following traumatic brain injury in aging NogoA/B-deficient mice. Neuroscience. 2009 Oct 6;163(2):540-51. Epub 2009 Jun [IF 3.4].-
Ekmark-Lewén S, Lewén A, Israelsson C, Li G-L, Farooque M, Olsson Y, Ebendal T, Hillered L (2010) Vimentin and GFAP responses in astrocytes after contusion trauma to the rat and mouse brain. Restorative neurology and neuroscience Jan 1; 28(3): 311-21 [IF 2.0]. -
Dahlin AP, Wetterhall M, Caldwell KD, Larsson A, Bergquist J, Hillered L and Hjort K (2010) Methodological aspects on microdialysis protein sampling and quantification in biological fluids – An in vitro study on human ventricular CSF. Anal Chem 82:4376-4385. [Epub ahead of print May 13] [IF 5.7].
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Hånell A, Clausen F, Björk M, Jansson K, Philipsson O, Lannfeldt L, Hillered L, Weinreb P, Lee D, McIntosh TK, Strittmatter SM, Marklund N (2010) Genetic Deletion and Pharmacological Inhibition of Nogo-66-Receptor Impairs Cognitive Outcome Following Traumatic Brain Injury in Mice. J Neurotrauma May 20 [E-pub ahead of print] [IF 4.3].
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Ekmark-Lewén S, Lewén A, Meyerson BJ, Hillered L (2010) The Multivariate Concentric Square Field Test Reveals Behavioral Profiles Regarding Risk Taking, Risk Assessment and Exploration in Mice Subjected to Traumatic Brain Injury. J Neurotrauma 27(9):1643-55; June 25 [Epub ahead of print] [IF 4.3].
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Clausen F, Hillered L, Gustafsson J (2011) Glucose metabolism after traumatic brain injury in the rat studied by 13C-glucose and microdialysis. Acta Neurochir (Wien) 153:653-658. [E-pub ahead of print Nov 21, 2010; IF 1,5].
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Marklund N, Hillered L (2010) Animal Modeling of Traumatic Brain Injury in Pre-clinical Drug Development - Where do we go from here? Br J Pharmacol Dec 22 (peer reviewed), [E-pub ahead of print, IF 5.2].
UBIC Dissertations
Hånell A (2011) Plasticity and Inflammation Following Traumatic Brain Injury. Diss Date 2011-04-01. http://uu.diva-portal.org/smash/record.jsf?pid=diva2:398436
Wallenquist U (2009) Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration.
Clausen, F (2004) Delayed cell death after traumatic brain injury: Role of reactive oxygen species. Diss Acta Univ Ups 1359.
Israelsson C (2006) Molecular Characterization of Experimental Traumatic Brain Injury. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine (ISSN 1651-6206) 163.
UBIC Collaborations
Centre of Excellence Neurotrauma
BrainIT
Uppsala Berzelii Technology Centre for Neurodiagnostics
