Traumatic brain injury (TBI) is a leading cause of morbidity and mortality that lacks specific therapy, in part because mechanisms that govern secondary brain injury are incompletely understood. Divergent modes of cell death, including necrosis, apoptosis, and caspase-independent programmed cell death have been demonstrated after experimental TBI, however mechanisms that initiate posttraumatic cell death are poorly understood. Tumor necrosis factor receptor (TNFR) family members (i.e., TNFR1, TNFR2, Fas) are transmembrane proteins involved in cell death, survival, and proliferation that are activated as part of an endogenous inflammatory response to TBI. Preliminary data strongly suggest that TNF alpha and Fas receptor, and discreet combinations of TNFR family members, promote caspase-3 activation, cell death, and motor and cognitive dysfunction after controlled cortical impact (CCI) in mice. We propose 3 Specific Aims to test the overall hypothesis that TNFR family members play key roles in the pathogenesis of TBI.
Aim 1 will test the hypothesis that inhibition of both TNF alpha and Fas receptor is required to reduce tissue damage and cognitive outcome after CCI.
Aim 2 will move downstream of TNF and identify TNFR combinations (TNFR1/Fas vs. TNFR2/Fas) that promote or inhibit cell death and functional recovery.
Aim 3 will identify mechanisms of TNFR-mediated cell death by examining activation of caspase-3 and the extrinsic death pathway (i.e., caspase-8, bid, cytochrome C) in TNF/Fas knockout mice. We will use novel mutant mice lacking TNF/Fas, TNFR1/Fas, orTNFR2/Fas; a novel propidium iodide labeling technique that detects acute posttraumatic cell death in the intact mouse brain; and state of the art image analysis and stereologic methods and equipment available in NIH-sponsored Imaging Core facilities. The goal of this revised proposal is to conclusively demonstrate that redundant and opposing effects of multiple TNFR family members integrate to significantly influence cell death, as well as motor and cognitive outcome, after TBI. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047447-02
Application #
7092556
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2005-09-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$361,306
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Saleh, Danish; Najjar, Malek; Zelic, Matija et al. (2017) Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-? Synthesis Induced by Lipopolysaccharide. J Immunol 198:4435-4447
Najjar, Malek; Saleh, Danish; Zelic, Matija et al. (2016) RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4. Immunity 45:46-59
Zhu, Xiaoxia; Park, Juyeon; Golinski, Julianne et al. (2014) Role of Akt and mammalian target of rapamycin in functional outcome after concussive brain injury in mice. J Cereb Blood Flow Metab 34:1531-9
Mannix, Rebekah C; Zhang, Jimmy; Berglass, Jacqueline et al. (2013) Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj 27:743-8
Dapul, Heda R; Park, Juyeon; Zhang, Jimmy et al. (2013) Concussive injury before or after controlled cortical impact exacerbates histopathology and functional outcome in a mixed traumatic brain injury model in mice. J Neurotrauma 30:382-91
Meehan 3rd, William P; Zhang, Jimmy; Mannix, Rebekah et al. (2012) Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice. Neurosurgery 71:885-91
Khuman, Jugta; Zhang, Jimmy; Park, Juyeon et al. (2012) Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice. J Neurotrauma 29:408-17
Park, Juyeon; Zhang, Jimmy; Qiu, Jianhua et al. (2012) Combination therapy targeting Akt and mammalian target of rapamycin improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 32:330-40
Mannix, Rebekah C; Zhang, Jimmy; Park, Juyeon et al. (2011) Detrimental effect of genetic inhibition of B-site APP-cleaving enzyme 1 on functional outcome after controlled cortical impact in young adult mice. J Neurotrauma 28:1855-61
Khuman, Jugta; Meehan 3rd, William P; Zhu, Xiaoxia et al. (2011) Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice. J Cereb Blood Flow Metab 31:778-89

Showing the most recent 10 out of 23 publications