Friday, July 26, 2024
7/26/2024
Diffuse traumatic brain injury (TBI) is associated with various pathologies that lead to long-term impairments, including post-traumatic headache (PTH), particularly migraine. There are worse outcomes of TBI when compounded with elevated intracranial pressure (ICP). The objective of the F99 work is to elucidate the mechanism(s) that may be attributed to TBI-induced pathologies and ICP-mediated diffuse pathologies. The objective of the K00 is to investigate cellular and molecular mechanisms of migraine to become an investigator of PTH in TBI. One pathology, neuronal membrane disruption, has been shown to be induced acutely post-TBI. However, my initial studies present that membrane disruption in neurons can last beyond the acute timeframe and last for weeks post-TBI. Furthermore, data indicate that there is a subpopulation of cortical neurons that do not express NeuN and are membrane disrupted. With other injuries, a NeuN negative (NeuN-) presentation has been indicative of a reversion to an immature neuronal phenotype. If injured neurons are reverting to an immature phenotype, then this could be a compensatory mechanism, so identifying these neurons that also are membrane disrupted may provide more insight into the molecular mechanism of membrane disruption. Aim 1a) is to investigate the identity of NeuN- subpopulation of membrane disrupted neurons using intracerebroventricular (ICV) cell impermeable fluorescently-tagged dextran tracer in sham and central fluid percussion injured (CFPI) animals. Then using histological and molecular paradigms, I will evaluate membrane disrupted neurons for cellular NeuN expression, and expression of immature neuronal markers. Incidentally, the mechanism behind neuronal membrane disruption is unknown, and previous work from our lab shows that when TBI is compounded with an elevation in ICP in rats, that neuronal membrane disruption is increased in direct relation to the ICP elevation. Aim 1b) is to evaluate the effects of secondary ICP elevation on the NeuN- membrane disrupted subpopulation. I propose that lysosomal Cathepsin B (Cath B) is a potential mediator of membrane disruption, as previous findings reveal that Cath B re-localizes from the lysosome to the cytosol, which has been shown by other groups to initiate cell damage/death. I intend to evaluate the effects of secondary ICP elevation on the NeuN- membrane disrupted population using sham, CFPI animals and CFPI+elevated ICP animals with the same dextran protocol aforementioned, via microscopic and molecular approaches. Simultaneously, I will investigate the role of Cath B in vivo by inhibiting Cath B following sham and injury then using activity assays to verify inhibition as well as microscopic studies to evaluate the re-localization of Cath B. I expect in the F99 project that diffuse TBI paired with elevated ICP will see increases in membrane disrupted population later. Yet, a reduction in the compensatory NeuN- subpopulation as these neurons will endure a secondary insult. Finally, it is expected that Cath-B is re-localizing from the lysosome to the cytosol after TBI in membrane disrupted neurons and will be exacerbated with secondary ICP insult.
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