• Biomarkers for traumatic brain injured patients

By using CSF and serum from our ADC BioBank, we developed a platform to identify and validate biomarkers of brain injury severity with proteomics approaches. We already discovered that active PERK is a serum marker of injury in humans (Fig. 4). This is a major contribution to the field, because there is a dire need for reliable biomarkers that distinguishes mild, moderate, severe, or lack of cognitive damage after head injury. This biomarker would dramatically modify therapeutic interventions to improve recovery.

 

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• Non-invasive imaging techniques to measure changes in neuronal function (supported by 5UL1TR000117-04, NIH/NCATS UK-CCTS – Pilot, and startup)

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We continue to expand on developing imaging approaches such as MEMRI. These imaging applications adapt emerging imaging technology to non-invasively enhance understanding of neuronal function and morphology. Based on our identification of imaging biomarkers of early neurodegeneration in preclinical models with MEMRI, I plan to leverage mangafodipir (chelated MnCl2) to look for signs of aging and disease as a quantitative metric for evaluating early diagnosis and the impact of pharmacological interventions.

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• PERK engagement of tau and its consequences for neuronal function (supported by NIH R01 NS091329-01A1)

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Use CRISPR/Cas9-generated mouse models to identify the mechanism by which disease-associated PERK SNPs mediated neuronal dysfunction. There are SNPs associated with progressive supranuclear palsy, but overexpression models on their own induce ER stress. We are currently working with Thermo to develop CRISPR-transgenic mice that express endogenous PERK with these SNPs. In addition, we will investigate the dynamics regulating PERK dimerization/tetramerization and its preferential engagement with substrates.