Grant: $22,314 - National Institutes of Health - Jul. 20, 2009
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Award Description: 'The Importance of Temperature on Inflammation after TBI': Traumatic brain injury (TBI) is a significant health concern affecting 1.4 million people in the United States at a cost of $56 billion dollars. Although much is known about the pathophisiological mechanisms underlying TBI, few therapeutic strategies have been successfully translated in the clinical setting to promote recovery. TBI initiates injury cascades including inflammatory processes that can serve to exacerbate the initial injury. Experimental findings from our laboratory as well as others have shown that post- traumatic temperature manipulations can significantly influence traumatic outcome as well as the inflammatory response to trauma. While post-traumatic hypothermia reduces the infiltration of polymorphonuclear leukocytes (PMNLs) into the brain and attenuates elevations in several pro-inflammatory cytokines, post-traumatic hyperthermia enhances these injury responses. The overall objective of this application is to identify the cellular, biochemical and molecular events associated with TBI that are sensitive to post-traumatic temperature manipulations. Thus, the proposed studies build on previous results and extend investigations into the cell signaling pathways underlying these temperature sensitive inflammatory events. The proposed studies will also assess the effects of post-traumatic temperature manipulations on a clinically relevant consequence of TBI, namely abnormal seizure activity. To this end, three specific aims are proposed that focus on questions regarding this investigative issue. In the first specific aim, we will investigate the effects of post-traumatic temperature manipulations on proinflammatory cytokine receptors and cytoplasmic intermediate involved in the early inflammatory response to TBI. In this aim Western blot analysis and immunocytochemistry will be used to document of IL-1b receptor and the down stream intermediates MKK4, MKK7, cJun, JNK, NF-kB, caspase-3, -8, and -9. In specific aim 2, experiments were proposed to determine the effects of temperature on the accumulation of inflammatory cells including PMNLs, monocytes/macrophages, T helper cells and microglia. A new battery of blood-brain barrier (BBB) probes will also be used to investigate the short and long term consequences of the temperature modifications on vascular permeability after trauma. In the final aim, experiments are proposed to determine the effects of post-traumatic temperature manipulations on seizure threshold. Behavioral, electrophysiological and immunocytochemical analysis will be used to investigate temperature sensitive mechanisms responsible for post-traumatic seizure activity.
Project Description: Traumatic brain injury (TBI) is known to cause long-lasting damage in the brain along with immediate damage after the initial impact. During this summer, the research assistant helped to further the research of this field by observing the temporal evolution of neurological damage by monitoring the MRI signal changes at different time points after moderate or severe parasagittal fluid-percussion in rats. By using high resolution MRI, diffusion tensor imaging, and perfusion weighted imaging, she continued research demonstrated from past studies that progressive atrophy in both gray and white matter structures may be related to chronic deficits in functional outcome. While at the Miami Project, the research assistant mainly worked with T2 Rare acquisition displaying anatomy and pathology at high resolution by defining regions of interest in order to gather data used for volumetric analysis. She diagramed several rat brains after either no, moderate, or severe TBI from the rostral to caudal regions at time points ranging from three days to one year, showing the development of atrophy over 12 months occurs mainly in the cortex and hippocampus. Her results demonstrated that fluid-percussion brain injury is associated with temporally and regionally specific MRI changes. The research assistamt was also dedicated to studying posttraumatic epilepsy and analyzing aberrant mossy fiber axonal sprouting in the hippocampus. She sectioned brain tissue using a freezing microtome and then performed Timm staining of the sections to analyze mossy fiber sprouting in the supragranular cell layer. After scoring the sprouting on a scale of 0-5 for all sham, TBI normothermic, and TBI hypothermic animals, it was found that most sprouting occurred in the normothermic TBI animals, which also developed significantly more posttraumatic seizures.
Jobs Summary: Prime recipient created one (1) summer student research assistant position, which was filled. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 20, 2009. Help expand these official descriptions using the wiki below.