Astroglial EAAT2 Changes in Live TBI Brain Determined by PET Imaging

PROJECT SUMMARYTraumatic Brain InjuryTBIis one of the most significant Public Health trauma diseases of our timeDiagnoses of various TBI forms rely on patient self reportingestablished clinical rating scalesand multimodality imaging to an extentTBI elicits complexheterogeneous pathological eventsincluding mechanical injuryhemorrhageand progressive secondary processes such as central and peripheral inflammation dynamics and excitotoxic driven necrotic and apoptotic eventsA focal contusion TBI model that recapitulates various aspects of TBI observed in human is the controlled cortical contusion impactCCIThe CCI rodent model can be used to determine longitudinal measures of TBI promoted neuropathological tissue changesThe major central nervous systemCNSneurotransmitter L glutamateL Glutargets the excitatory amino acid transporterEAATthat clearsof synaptic L GluEAATis expressed throughout the CNS and is primarily found on astroglialastrocytecell membranesSpatiotemporal changes to CNS EAATprotein densities are found in TBI postmortem brain tissuesincluding those from rodent TBI models wherereductions of EAATis observed at acute times after injuryPositron emission tomographyPETimaging is a technique that is sensitive and quantitative at the molecular level where it uniquely determines a positron labeled tracer binding potential to its targeted CNS proteinthereby quantifying target protein density in live CNS tissuesA first in class fluorinelabeledFtracer known asF FAA has been discovered and possesses outstanding in vivo PET imaging qualities for quantitative determinations of CNS astrocyte EAATtarget protein densities in live brainRio PharmaceuticalsInchas licensed this EAATPET imaging tracer technology and is further developing it for eventual clinical useIt is thought that the EAATtracer is suitable to mark severity and localization of TBI in live brainWe hypothesize that CCI promoted traumatic brain injury results in acute and latent regional cerebral tissue pathologies that can be marked in vivo by determining CNS EAATprotein density changes measured by quantitative dynamic PET imaging and correlated to in vitro regional cerebral tissue EAATand GFAP density alterations over timeOur long term objective is to advance the development of a quantitative PET imaging tracer for CNS EAATastrocyte protein target as an effective marker of TBI severity and localizationUltimatelyclinical EAATCNS PET imaging will aid quantitative TBI diagnoses and afford a means to follow CNS tissue changes as a result of novel TBI therapiesThe goal of this Phaseinvestigation is to establish an initial proof of conceptPOCdemonstrating that dynamic PET imaging of the astrocyte EAATtarget protein in live CCI TBI rat brain is a quantitative marker of TBI severity and localizationEstablishing the PhasePOC will permit subsequent Phasetracer development investigation in both males and female rodentswith experiments to further interrogate EAATin model TBI braine gCCI and closed head concussive injuryand studies to satisfy FDA criteria for evaluation of the PET imaging technology for clinical safety and TBI use efficacyThe industrial academic collaborative PhasePOC project goal will be accomplished with the following three specific aims over one yearSpecific AimEvaluate cerebral PET CT MR imaginganddays after controlled CCI to afford quantitative cerebral signatures ofF FAA tracer binding potentials to EAATtargetSpecific AimMeasure regional cerebral EAATand GFAP densities and the expression profiles of related markers in postmortem rat brain tissuesanddays after CCI TBI injurySpecific AimEstablish the PhasePOC by determining correlations between regional in vivo EAATPET imaging tracer binding potential values and postmortem EAATand GFAP measures PROJECT NARRATIVETraumatic brain injuryTBIis one of the most significant Public Health trauma diseases of our time and it leads to long term disabilitiesThe central nervous systemCNSinjury is mechanical and alters brain tissue resulting in hemorrhage and secondary processes that are dynamic over timeRodent models are used to better understand the tissue neuropathology associated with TBIThe models serve as platform for the discovery of new TBI therapiesof which there are fewOne insightful model is the controlled cortical contusion impactCCIinjury model elicited by mechanical compression on skull opened rodentsIn an effort to interrogate live rodent CCI TBI brainthe research is focused on examining the CNS protein known as the excitatory amino acid transporterEAATthat is found on astrocyte cell membranes and removes the major neurotransmitter glutamate from the synaptic cleftFrom postmortem research studieschanges to CNS EAATprotein densities occur with TBI injuryThe investigation will utilize a new radiolabeled tracer drug known asF FAA with positron emission tomographyPETimagingin order to evaluate the effectiveness of detecting EAATchanges in live tissues of rodent CCI TBI brain over time with comparisons to parallel determinations within collected postmortem CCI TBI rodent CNS tissuesThe Phaseproject will establish a proof of concept thatF FAA tracer with PET imaging effectively marks the severity and localization of TBI in live model TBI rodent brain