This application seeks to continue 20 years of support focusing on the microvascular, neuronal somatic, axonal and deafferentation-mediated responses to traumatic brain injury. In previous funding periods, we have shown that the injury does not tear axons. Rather, it triggers local axonal damage that leads to continued alteration and ultimate disconnection. It has been assumed by all that once disconnected the proximal axonal tip swells, due to the delivery of substances via anterograde transport, with the resulting axonal bulb formation becoming the universally recognized endpoint for all contemporary forensic, neuropathological and experimental studies. Recently, our laboratory has suggested that many injured axons may not progress to bulb formation, which suggests differing modes of pathogenesis and potential therapeutic modulation. In this application we focus on this issue using different animal models of TBI, employing lissencephalic and gyrencephalic species. The resulting TAI will be followed over time by double label immunocytochemical strategies targeting various cytoskeletal, axolemmal and axonal transport abnormalities. Quantitative, computer-assisted EM analysis will be used to better understand the precise subcellular changes associated with TIA as well as the mechanisms related thereto. Moving on the premise that we will observe different populations of injured axons, with differing forms of pathogenesis, we will also pursue descriptive and mechanistic studies related to their response to agents reported to attenuate TAI. Cyclosporin A and FK506 will be used in addition to hypothermia to assess their impact on these differing forms of TAI via the same strategies noted above. These studies will be interfaced with electrophysiological and neurochemical assessments to examine any therapeutic modulation of action potentials, calcineurin activity or mitochondrial function. The successful conduct of these studies should provide new insight into the complex pathobiology of TAI and its therapeutic modulation.
Showing the most recent 10 out of 62 publications
