Traumatic Brain Injury Research Laboratory

Traumatic brain injury is the leading cause of death in children and accounts for over 50,000 deaths in the United States each year.  Survivors are left with lifelong motor and cognitive deficits and suffer from neuropsychiatric sequelae such as depression and PTSD, as well as from memory impairment and depressed executive functioning.  To date, there is no specific treatment for the neurological sequelae of severe brain trauma; therapy is directed toward reduction of intracranial pressure and maintaining physiological homeostasis.  Similarly, non-traumatic intracerebral hemorrhage (ICH), accounting for 15% of all strokes, has a high mortality rate and no specific therapy to improve outcome in survivors.  We use adult and pediatric TBI and ICH models and concentrate our studies in the following categories:

• Role of tumor necrosis factor receptor superfamily components in the pathogenesis of cerebral contusion and concussion TBI.   
• Role of programmed necrosis (necroptosis mediated by RIPK1) in the pathogenesis of cell death and cognitive outcome after cerebral contusion and ICH
• Secondary injury mechanisms that mediate cognitive dysfunction after single and multiple concussion TBI
• Role of the APOE4 genotype in cognitive outcome after concussion
• Membrane resealing agents to reduce blood brain barrier damage and brain edema after contusion TBI
• Role of CCR2 and CX3CR1 in the pathogenesis of cognitive dysfunction after contusion and concussion TBI and ICH
• Low level laser light photobiomodulation to reduce cognitive deficits after TBI
• Development of an immature and adult mouse models of concussion TBI

Our approach includes the use of genetically modified mice, viral vector gene transduction, standard molecular techniques, cell death studies, and mouse behavioral assessments including fear learning and extinction to assess the PTSD phenotype and its interaction with TBI.  Major funding sources are the NIH/NINDS, DOD, and NFL Charities Foundation.  We are affiliated with the MGH Neuroscience Center.

Biography

Dr. Whalen received his MD degree from the University of Vermont, Burlington, VT, and residency training in Pediatrics at Medical College of Virginia, VA. He trained in Pediatric Critical Care at the Pittsburgh Children's Hospital, Pittsburgh, PA, before joining MassGeneral Hospital for Children in 1999.

Research Program

Mission statement: I am a pediatric intensivist who cares for critically ill children with brain injury.  The goal of my laboratory is to discover molecular mechanisms that lead to neurological dysfunction after acute brain injury, and to develop therapies to improve outcome after traumatic brain injury and stroke.  Today, despite many advances in technology and medicine, treatment for children with acute brain injury remains supportive and is focused on controlling intracranial pressure. There are no specific treatments proven to enhance neurological recovery from injury, in large part due to incomplete understanding of the cellular and molecular mechanisms that determine neurological outcome. My research career is dedicated to elucidating these mechanisms, and in so doing uncover new therapeutic targets to prevent or reduce neurological sequelae of acute brain injury.

To this end my laboratory has developed and published new mouse models of concussion that replicate mechanical mechanisms (impact plus whiplash components) and lack of structural brain injury observed in humans.  These mouse models feature single and repetitive injury and result in long term cognitive deficits.  We are currently focused on the role of RIPK1 and innate immune signaling as potential drivers of postinjury cognitive dysfunction in cerebral contusion and concussion models, as well as intracerebral hemorrhage.  We have brought several new potential therapeutic agents to preclinical testing including necrostatins (RIPK1 inhibitors) and VA64 (a polymer that reduces brain edema in cerebral contusion and water intoxication models) and are currently working on resolvins and other inflammation modulating agents, as well as targeting Akt/mTOR pathways in cerebral contusion models.

In addition to discovering disease mechanisms, my laboratory is committed to training the next generation of PhD and physician scientists.  We have had many students obtain their Master’s and PhD degrees while working in our laboratory, and we have provided research training and mentorship to undergrad and post-graduate students who have gone on to medical school.  As a physician scientist I am in a unique position to help trainees advance their careers in science and medicine.

Collaborators

• Dr. Joseph El Khoury – Massachusetts General Hospital, Center for Inflammatory Diseases
• Dr. Eng Lo – Massachusetts General Hospital, Department of Radiology and Neurology
• Dr. David Boas- MGH Martinos Center
• Dr. Emad Eskandar- MGH Neurosurgery (Deep Brain Stimulation)
• Dr. Mohammed Milad- MGH Psychiatry
• Dr. Alexei Degterev – Tufts University, Sackler School of Graduate Biomedical Sciences, Developmental, Molecular and Chemical Biology
• Dr. Junying Yuan- Harvard Cell Biology Program
• Dr. David Kaplan – Tufts University, Department of Biomedical Engineering
• Dr. Srinivas Sridhar- Northeastern University Nanomedicine Program

Current Members

• Dr. Michael Whalen, MD – Principle Investigator
• Dr. Sevda Lule, PhD- Postdoctoral Fellow
• Dr. Jessica Hahn, MD- PICU Fellow
• Lauren McAllister, BA – Behavioral Research Technician
• Joon Chung – Technician, University of Massachusetts Amherst
• Josephine Pucci – Volunteer, Harvard University and member 2014 US Women’s Olympic Hockey Team

• Development of mouse models of concussion in adolescents and adults
• Innate immunity as a driver of cognitive dysfunction in adolescent mouse concussion models
• Mechanisms of programmed necrosis and innate immunity after intracerebral hemorrhage: Role of RIPK and associated proteins
• Deep Brain Stimulation to improve functional outcome after Traumatic Brain Injury
• Mechanisms of programmed necrosis after traumatic brain injury
• Biomaterials to treat and model traumatic brain injury in vitro and in vivo
• Use of NIRS and diffuse correlation spectroscopy to assess cerebral blood flow and metabolism changes as predictors of outcome after repetitive concussions in mice
• Metabolomics analyses of blood and brain after repetitive concussions in mice
• Studies of the association between TBI and PTSD using mouse models

Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation.
Schaefer JH, Leung W, Wu L, Van Cott EM, Lok J, Whalen M, van Leyen K, Lauer A, van Ryn J, Lo EH, Foerch C.
J Cereb Blood Flow Metab. 2014 Feb 19. doi: 10.1038/jcbfm.2014.31.

Response to laskowitz and dawson.
Mannix R, Meehan WP, Feany M, Grant PE, Mandeville J, Kaplan DL, Whalen M.
Ann Neurol. 2013 Nov 16. doi: 10.1002/ana.24056.

Akt and mTOR mediate programmed necrosis in neurons.
Liu Q, Qiu J, Liang M, Golinski J, van Leyen K, Jung JE, You Z, Lo EH, Degterev A, Whalen MJ.
Cell Death Dis. 2014 Feb 27;5:e1084. doi: 10.1038/cddis.2014.69.

Beneficial effect of amyloid beta after controlled cortical impact.
Mannix RC, Zhang J, Berglass J, Qui J, Whalen MJ.
Brain Inj. 2013 Jun;27(6):743-8. doi: 10.3109/02699052.2013.771797.

Concussive injury before or after controlled cortical impact exacerbates histopathology and functional outcome in a mixed traumatic brain injury model in mice.
Dapul HR, Park J, Zhang J, Lee C, DanEshmand A, Lok J, Ayata C, Gray T, Scalzo A, Qiu J, Lo EH, Whalen MJ.
J Neurotrauma. 2013 Mar 1;30(5):382-91. doi: 10.1089/neu.2012.2536.

Depletion of GGA1 and GGA3 mediates postinjury elevation of BACE1.
Walker KR, Kang EL, Whalen MJ, Shen Y, Tesco G.
J Neurosci. 2012 Jul 25;32(30):10423-37. doi: 10.1523/JNEUROSCI.5491-11.2012.

Neuregulin-1 effects on endothelial and blood-brain-barrier permeability after experimental injury.
Lok J, Zhao S, Leung W, Seo JH, Navaratna D, Wang X, Whalen MJ, Lo EH.
Transl Stroke Res. 2012 Jul;3 Suppl 1:S119-24. doi: 10.1007/s12975-012-0157-x. 

Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice.
Meehan WP 3rd, Zhang J, Mannix R, Whalen MJ.
Neurosurgery. 2012 Oct;71(4):885-91.

Neuroglobin-overexpression reduces traumatic brain lesion size in mice.
Zhao S, Yu Z, Zhao G, Xing C, Hayakawa K, Whalen MJ, Lok JM, Lo EH, Wang X.
BMC Neurosci. 2012 Jun 15;13:67. doi: 10.1186/1471-2202-13-67.

Traumatic brain injury, microglia, and Beta amyloid.
Mannix RC, Whalen MJ.
Int J Alzheimers Dis. 2012;2012:608732. doi: 10.1155/2012/608732. Epub 2012 May 14.

Neurovascular matrix metalloproteinases and the blood-brain barrier.
Seo JH, Guo S, Lok J, Navaratna D, Whalen MJ, Kim KW, Lo EH.
Curr Pharm Des. 2012;18(25):3645-8. Review.

Low-level laser therapy for closed-head traumatic brain injury in mice: effect of different wavelengths.
Wu Q, Xuan W, Ando T, Xu T, Huang L, Huang YY, Dai T, Dhital S, Sharma SK, Whalen MJ, Hamblin MR.
Lasers Surg Med. 2012 Mar;44(3):218-26. doi: 10.1002/lsm.22003. Epub 2012 Jan 24.

Traumatic brain injury during warfarin anticoagulation: an experimental study in mice.
Foerch C, You Z, Wang H, Lo EH, Whalen MJ.
J Neurotrauma. 2012 Apr 10;29(6):1150-5. doi: 10.1089/neu.2011.2104.

Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice.
Mbye LH, Keles E, Tao L, Zhang J, Chung J, Larvie M, Koppula R, Lo EH, Whalen MJ.
J Cereb Blood Flow Metab. 2012 Mar;32(3):515-24. doi: 10.1038/jcbfm.2011.158.

Plasmalemma permeability and necrotic cell death phenotypes after intracerebral hemorrhage in mice.
Zhu X, Tao L, Tejima-Mandeville E, Qiu J, Park J, Garber K, Ericsson M, Lo EH, Whalen MJ.
Stroke. 2012 Feb;43(2):524-31. doi: 10.1161/STROKEAHA.111.635672. 

Comparison of therapeutic effects between pulsed and continuous wave 810-nm wavelength laser irradiation for traumatic brain injury in mice.
Ando T, Xuan W, Xu T, Dai T, Sharma SK, Kharkwal GB, Huang YY, Wu Q, Whalen MJ, Sato S, Obara M, Hamblin MR.
PLoS One. 2011;6(10):e26212. doi: 10.1371/journal.pone.0026212. 

Neuronal deletion of caspase 8 protects against brain injury in mouse models of controlled cortical impact and kainic acid-induced excitotoxicity.
Krajewska M, You Z, Rong J, Kress C, Huang X, Yang J, Kyoda T, Leyva R, Banares S, Hu Y, Sze CH, Whalen MJ, Salmena L, Hakem R, Head BP, Reed JC, Krajewski S.
PLoS One. 2011;6(9):e24341. doi: 10.1371/journal.pone.0024341.

Combination therapy targeting Akt and mammalian target of rapamycin improves functional outcome after controlled cortical impact in mice.
Park J, Zhang J, Qiu J, Zhu X, Degterev A, Lo EH, Whalen MJ.
J Cereb Blood Flow Metab. 2012 Feb;32(2):330-40. doi: 10.1038/jcbfm.2011.131. 

Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice.
Khuman J, Zhang J, Park J, Carroll JD, Donahue C, Whalen MJ.
J Neurotrauma. 2012 Jan 20;29(2):408-17. doi: 10.1089/neu.2010.1745.

Detrimental effect of genetic inhibition of B-site APP-cleaving enzyme 1 on functional outcome after controlled cortical impact in young adult mice.
Mannix RC, Zhang J, Park J, Lee C, Whalen MJ.
J Neurotrauma. 2011 Sep;28(9):1855-61. doi: 10.1089/neu.2011.1759.

Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice.
Khuman J, Meehan WP 3rd, Zhu X, Qiu J, Hoffmann U, Zhang J, Giovannone E, Lo EH, Whalen MJ.
J Cereb Blood Flow Metab. 2011 Feb;31(2):778-89. doi: 10.1038/jcbfm.2010.172. Epub 2010 Oct 13.

Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice.
Mannix RC, Zhang J, Park J, Zhang X, Bilal K, Walker K, Tanzi RE, Tesco G, Whalen MJ.
J Cereb Blood Flow Metab. 2011 Jan;31(1):351-61. doi: 10.1038/jcbfm.2010.99. Epub 2010 Jun 30.

Genetic analysis of the role of tumor necrosis factor receptors in functional outcome after traumatic brain injury in mice.
Yang J, You Z, Kim HH, Hwang SK, Khuman J, Guo S, Lo EH, Whalen MJ.
J Neurotrauma. 2010 Jun;27(6):1037-46. doi: 10.1089/neu.2009.1229.

Diffusion-weighted magnetic resonance imaging reversal by gene knockdown of matrix metalloproteinase-9 activities in live animal brains.
Liu CH, You Z, Liu CM, Kim YR, Whalen MJ, Rosen BR, Liu PK.
J Neurosci. 2009 Mar 18;29(11):3508-17. doi: 10.1523/JNEUROSCI.5332-08.2009.