Spinal cord injury (SCI) is a devastating condition that has disabled millions of individuals world-wide. Pathophysiologically, its two principal components are the acute tissue damage directly associated with the inciting injury, and a later phase of delayed injury that occurs over the ensuing days. This latter phase is primarily a consequence of inflammation and inflammatory edema, which reduces parenchymal perfusion, thereby resulting in ischemic extension of the initial injury. Remarkably, this delayed inflammatory injury may lead to more structural damage than the initial injury, and typically accounts for the bulk of neurological morbidity in SCI patients. Most contemporary studies have focused on the late effectors of this inflammatory response; few have sought to identify the upstream initiators of this process. This proposal will thus test the novel postulate that the inflammatory response to traumatic SCI is initiated by astrocytic ATP release, which serves to activate local microglia in a purine receptor-dependent fashion; subsequent inflammatory effectors are released in the setting of this secondary microglial response. The proposal is based on our preliminary observations that traumatic SCI is associated with the pathological release of ATP, and that purinergic receptor antagonists effectively reduced inflammation and improved locomotor recovery after SCI.
Aim 1 will test the postulate that the dysregulated post-traumatic release of ATP is both necessary and sufficient for microglial activation. These experiments will employ novel transgenic mice that have been engineered to release either abnormally high or low levels of astrocytic ATP in response to SCI: ATP release is attenuated in mice lacking astrocytic connexin hemichannels (Cx43/Cx30 KO), but potentiated in mice with an increased number of astrocytic hemichannels (Cx43 G138R mutation).
Aim 2 will attempt to define the pathway intermediates downstream of purinergic activation in the post-traumatic inflammatory response. The effects of genetic and pharmacological manipulations of purinergic signaling on the transcriptional activation of both chemokine and cytokine effectors of SCI will be assessed, so as to define the pathways by which the inflammatory sequelae of purinergic activation are coordinated. Transcriptional changes in microglial gene expression will be analyzed by microarray assessment of FACS-sorted microglia.
Aim 3 will then test the idea that microglial inflammatory mediators trigger astrogliosis and hence astroglial scar formation, which in turn provides the nidus for a sustained increase in local ATP release. As such, this Aim will test the possibility that astrocytic ATP release is increased for weeks to months following SCI. Our hypothesis is that the ATP released from reactive astrocytes may drive the further release of pro-inflammatory mediators, thereby enhancing astrogliosis. Together, these experiments promise to fill critical gaps in our understanding of the role of purinergic signaling in SCI, and should permit us to define purine-regulated genes and gene products critical that might permit the therapeutic suppression of delayed spinal cord injury.
This project will link ATP release and purinergic signaling to microglial cell activation and release of inflammatory agents following spinal cord injury. Our goal is to define targets for development of novel therapeutic to treat acute spinal cord injury.
|Ratner, Vadim; Gao, Yi; Lee, Hedok et al. (2017) Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport. Neuroimage 152:530-537|
|Wang, Minghuan; Ding, Fengfei; Deng, SaiYue et al. (2017) Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts. J Neurosci 37:2870-2877|
|Wang, Fushun; Wang, Xiaowei; Shapiro, Lee A et al. (2017) NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility. Brain Struct Funct 222:1543-1556|
|Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2017) Erratum to: Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 12:3|
|Lundgaard, Iben; Lu, Minh Lon; Yang, Ezra et al. (2017) Glymphatic clearance controls state-dependent changes in brain lactate concentration. J Cereb Blood Flow Metab 37:2112-2124|
|Cotrina, Maria L; Lou, Nanghong; Tome-Garcia, Jessica et al. (2017) Direct comparison of microglial dynamics and inflammatory profile in photothrombotic and arterial occlusion evoked stroke. Neuroscience 343:483-494|
|Sun, Wei; Cornwell, Adam; Li, Jiashu et al. (2017) SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions. J Neurosci 37:4493-4507|
|Jiang, Quan; Zhang, Li; Ding, Guangliang et al. (2017) Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab 37:1326-1337|
|de Leon, Mony J; Li, Yi; Okamura, Nobuyuki et al. (2017) Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J Nucl Med 58:1471-1476|
|Kjaerby, Celia; Rasmussen, Rune; Andersen, Mie et al. (2017) Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function? Neurochem Res 42:1810-1822|
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