In this proposal, we will use a mouse model of controlled cortical impact to test the idea that secondary cell death after traumatic brain injury is mediated by matrix metalloproteinases (MMP) which disrupt cell-matrix and cell-cell interactions, thus triggering apoptosis in brain regions beyond the site of original impact. Our working hypothesis states that: 1) mechanical stress induced by trauma activate MAP kinase signal transduction pathways, 2) MAP kinease pathways upregulate MMP expression, 3) MMP disrupts the extracellular matrix, and 4) disruption of cell-matrix and cell-cell interactions lead to apoptotic cell death. Preliminary data show that (a) the mouse model of controlled cortical impact is stable and reproducible in our lab; (b) western blots from traumatized brain show activation of the MAP kinase pathways ERK and SAPK2/p38; (c) the ERK/MAP kinase pathway upregulates MMP in vitro; (d) MMP activation occurs after trauma in vivo; (e) knockout mice deficient in MMP-9 show reduced injury after stroke and trauma, (f) direct injection of MMP-7 into mouse brain induces apoptosis; and (g) inhibition of the ERK/MAP kinase pathway reduces injury after stroke. We will extend our preliminary findings by pursuing the following specific aims. 1. Define the signaling pathways that lead to MMP upregulation and apoptosis after trauma. MMP gene promoter regions contain AP1 sites. Therefore, we propose that upstream activators of MMP involve MAP kinase signal transduction pathways. We will map the regional and temporal profiles of three major MAP kinsaes after trauma: ERK, SAPK1/JNK, and SAPK2/p38. Correlations between MAP kinase pathways, MMP expression , matrix disruption and apoptotic cell death will be assessed. 2. Characterize the role of specific MMP after trauma. We will examine morphological, biochemical and behavioral responses to trauma in MMP-2, MMP-7 and MMP-9 knockout mice, and transgenic mice overexpressing tissue inhibitor of MMP (TIMP-1). 3. Test the Neuroprotective effects of inhibitors of the ERK pathway (PD98059, U0216), p38 pathway (SB203580) and MMP (BB-94) for traumatic brain injury. Both morphological and behavioral outcomes will be measured. To date, there are not effective treatments for traumatic brain injury. Results from these proposed experiments will help identify MMP and upstream MAP kinase pathways as viable therapeutic targets for this devastating condition.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (04))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Hayakawa, Kazuhide; Pham, Loc-Duyen D; Som, Angel T et al. (2011) Vascular endothelial growth factor regulates the migration of oligodendrocyte precursor cells. J Neurosci 31:10666-70
Ning, Mingming; Wang, Xiaoying; Lo, Eng H (2009) Reperfusion injury after stroke: neurovascular proteases and the blood-brain barrier. Handb Clin Neurol 92:117-36
Kelly, Peter J; Morrow, Jason D; Ning, MingMing et al. (2008) Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 39:100-4
Lee, S-R; Lok, J; Rosell, A et al. (2007) Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. Neuroscience 150:50-7
Lok, Josephine; Gupta, Punkaj; Guo, Shuzhen et al. (2007) Cell-cell signaling in the neurovascular unit. Neurochem Res 32:2032-45
Bermpohl, Daniela; You, Zerong; Lo, Eng H et al. (2007) TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice. J Cereb Blood Flow Metab 27:1806-18
Tejima, Emiri; Zhao, Bing-Qiao; Tsuji, Kiyoshi et al. (2007) Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 27:460-8
Zhao, Bing-Qiao; Tejima, Emiri; Lo, Eng H (2007) Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke 38:748-52
Ning, M; Furie, K L; Koroshetz, W J et al. (2006) Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 66:1550-5
Lee, Seong-Ryong; Kim, Hahn-Young; Rogowska, Jadwiga et al. (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26:3491-5

Showing the most recent 10 out of 41 publications