Principal Investigator/Program Director (Last, first, middle): Whalen, Michael, Jerome RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 10-20-2006 Animal Welfare Assurance Number A3596-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: IACUC protocol number 2004N000286 6. * Project Summary/Abstract 4252-Abstractfinal.pdf Mime Type: application/pdf 7. * Project Narrative 6675-Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 5486-Bibliography.pdf Mime Type: application/pdf 9. Facilities &Other Resources 3019-FacilitiesResources.pdf Mime Type: application/pdf 10. Equipment 6719-Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Whalen, Michael, Jerome A fundamental problem in the neuroprotection field that remains unsolved is whether or not traumatically injured brain cells can be rescued from death. Essential concepts such as survival time and functionality of injured cells, and the """"""""point of no return"""""""" from eventual demise have not been adequately explored in traumatic brain injury (TBI) models. Loss of plasmalemma integrity is a common feature of cellular injury and death in experimental TBI. Using propidium iodide (PI) to label cells with loss of plasmalemma integrity in vivo, we developed a PI pulse labeling protocol to follow the fate of injured brain cells after controlled cortical impact (CCI) in mice. Our findings suggest that although loss of plasmalemma integrity is a biomarker of fatal injury in many cells, a subset of PI+ cells may be rescuable by appropriate therapeutic agents. Based on these data, we propose three Specific Aims to test the central hypothesis that loss of plasmalemma integrity is a therapeutic target to rescue injured cells after TBI:
Aim 1 : Test the hypothesis that loss of plasmalemma integrity early versus late following controlled cortical impact is a biomarker of fatal versus rescuable injury, respectively.
Aim 2 : Test the hypothesis that loss of plasmalemma integrity is an active process mediated by TNF alpha and Fas receptors beginning early (minutes) after TBI, using in vitro and in vivo trauma models and mice or primary cortical neurons deficient in TNF/Fas.
Aim 3 : Test the hypothesis that restoration of plasmalemma integrity is a therapeutic target to rescue traumatically injured brain cells after CCI. Use poloxamer P188, a non-ionic amphiphilic triblock copolymer membrane resealing agent, and necrostatin-1, a specific inhibitor of TNF/Fas induced cell death, to reduce plasmalemma damage and acute cell death and improve functional outcome after CCI in mice. The proposed studies are intended to show that loss of plasmalemma integrity is a therapeutic target to rescue injured cells in patients with TBI. Project Description Page 6
| Miller, Benjamin F; Keles, Eyup; Tien, Lee et al. (2014) The pharmacokinetics and pharmacodynamics of Kollidon VA64 dissociate its protective effects from membrane resealing after controlled cortical impact in mice. J Cereb Blood Flow Metab 34:1347-53 |
| Mbye, Lamin H; Keles, Eyup; Tao, Luyang et al. (2012) Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 32:515-24 |
| Zhu, Xiaoxia; Tao, Luyang; Tejima-Mandeville, Emiri et al. (2012) Plasmalemma permeability and necrotic cell death phenotypes after intracerebral hemorrhage in mice. Stroke 43:524-31 |
| You, Zerong; Savitz, Sean I; Yang, Jinsheng et al. (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 28:1564-73 |
