CAREER: An engineered nanosensor to measure in vivo protease activity in traumatic brain injury

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Traumatic brain injury (TBI) affects millions of Americans annually. A major challenge in the development of TBI therapies is an incomplete understanding of the progressive disease that is initiated by TBI. Therefore, the goal of this CAREER award is to engineer technology to measure TBI-associated activity and use this technology to understand the molecular mechanisms that underlie TBI. New understanding of TBI-associated molecular mechanisms can guide the development of new therapies for TBI and other brain disorders. The research will provide research-based training opportunities for a diverse group of undergraduate and graduate students to prepare them to enter the science technology engineering and mathematics (STEM) workforce. Ideas and concepts from the research will be incorporated into lesson plans in collaboration with high school teachers in order to promote broad participation in STEM fields. One existing challenge in the development of new therapeutics and clinical management of TBI is a lack of biomarkers that can measure the severity of disease and predict long-term outcomes. Proteases are key molecules in TBI disease progression and are candidates for therapeutic inhibition in TBI. Therefore, the measurement of TBI-associated protease activity may be critical to understand long-term biological outcomes and provide a greater understanding of disease. However, currently, there are no tools to measure protease activity in a living organism after TBI. The goal of this CAREER proposal is to engineer technology to measure protease activity in vivo and study the role of protease activity in TBI disease progression and therapeutic treatment. As a second goal, the technology will also be developed as a diagnostic to complement existing diagnostic paradigms in TBI. The proposed ‘nanosensor’ technology that will be developed is based on the ability of nanometer scaled materials to passively accumulate into the injured brain across the damaged blood-brain barrier and respond to elevated protease activity after TBI. Design criteria that will be engineered into the nanosensor include the ability to detect multiple proteases, be measured from biological fluids, and be actively targeted. The technology will be used to study protease activity in response to varying severities of TBI and in the presence of pharmacologic inhibition. The nanosensor will also be designed to integrate with a paper-based assay for a low-resource, rapid readout as a diagnostic tool that complements existing imaging and behavioral diagnostics in the clinic. This research will yield a multiplexed and targeted nanoscale sensor of protease activity. Due to the integral role proteases have across multiple diseases, including infectious diseases, tools to measure protease activity and a greater understanding of protease activity in disease have the potential to be broadly applicable.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.