CAREER: Diagnosing the Undiagnosable: Using Enzyme Upregulation to Probe Cellular Behavior in Neuropathic Lysosomal Storage Disease

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The objective of this project is to develop a method to non-invasively diagnose a rare and fatal brain disease, GM1 gangliosidosis, using polymeric nanoparticles called polymersomes. The development of this polymersome tool will provide real-time information on the disease progression of the patient, allowing for better clinical interventions. The work will identify the potential of enzyme activities as biomarkers of GM1 disease progression in cellular and animal models. The polymersomes will provide real-time fluorescent read outs in the brains of mice, which correlate with these enzyme activity levels and confirm disease progression. The research objectives of the CAREER project are integrated with educational objectives to engage high school teachers in research and increase their knowledge of the scientific process. Our CoME and SEE SC program will integrate this research experience with guided development of in-class modules that teachers will bring back to their students to increase civic scientific literacy in South Carolina.The overarching career goal of the investigator is to understand the interactions of polymers with the central nervous system. Towards this goal, this CAREER project aims to create a nanoparticle system of stimuli-responsive polymers (polymersomes) that alter their structure in response to pathological changes associated with brain disease to improve diagnosis. Specifically, this proposal focuses on elucidating homeostatic changes related to GM1 gangliosidosis, a lysosomal storage disorder in drastic need of a diagnostic and monitoring tool. Diagnosis and monitoring can be improved by understanding the relationship between cellular changes and enzyme activity throughout disease progression, validating enzyme activity as a biomarker of disease. Simultaneously, we develop a biohybrid polymersome system, responding and degrading in the presence of enzymes, to provide a diagnostic measure. Unlike current techniques, executed at single time points only, this novel biohybrid system will enable the acquisition of temporospatial information in situ in the brain. Finally, the modular nature of this tool will permit small changes to create diagnostic opportunities throughout the brain, laying a foundation for measuring in situ levels of many macromolecules in patient brains. The research aims integrate with the educational goal of increasing the scientific literacy and attitudes towards the nature of science of citizens in the state of South Carolina. The project activities aim to create scientific citizens that feel comfortable making science-related policy decisions (civic scientific literacy). The proposed program, CoME and SEE SC, provides high school teachers with professional development, coupled with research, to increase their civic scientific literacy, which will translate to students.This project is jointly funded by Engineering of Biomedical Systems (EBMS) and the Established Program to Stimulate Competitive Research (EPSCoR).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.