Traumatic brain injury (TBI) is a leading cause of disability in the elderly. The outcome of a similar injury is worse in the elderly than in younger adults, but the mechanisms underlying this difference are unknown. An interdisciplinary research team including a biomedical engineer with expertise in high field strength MRI, an expert on human TBI, and a neuroscientist with expertise in molecular and behavioral neuroscience will address the hypothesis that increased inflammatory responses to a comparable injury in old mice contribute to the worsened outcome. The experiments test the specific mechanistic hypothesis that in old mice, an increased inflammatory response causes increased activation of the extrinsic apoptosis pathway and increased activation of stress kinase JNK, both of which result in increased secondary neuron death. Preliminary data support this hypothesis by demonstrating higher expression of proinflammatory genes in old than in adult mice during secondary neuron death.
Two specific aims are proposed to test this hypothesis: 1) Develop a model of mild controlled cortical impact (CCI) in mice to model contusional TBI, characterize initial behavioral deficits and recovery using cognitive and motor tests, characterize tissue damage and neuron death after CCI in adult and old mice by MRI, histology and unbiased stereology, and assays of activation of the effector caspase-3, and 2) Characterize the inflammatory response by measuring expression of proinflammatory genes including MCP-1, TNF-alpha, and IL-1beta in cortex, hippocampus and thalamus, determine whether the response to CCI in old mice involves increased activation of the stress kinase JNK, and determine whether the response to CCI in old mice involves increased activation of the extrinsic apoptosis pathway via caspase-8. The overall goal of these studies is to provide a rationale for specific treatments for TBI in the elderly. ? ? ?
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