CAREER: Quantitative Tools to Measure the Spatiotemporal Dynamics of Protein Signaling Complexes

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Though more than 10 million people in the USA suffer from learning and memory disorders, the underlying causes of many of these disorders are still not clear. Most of these disorders arise due to disruptions in the regulation of protein networks (called protein signaling complexes) that control the strength of the connections (called synapses) that allow neurons to communicate with each other. Using sophisticated computer modeling and super-resolution microscopes, this project seeks to produce significant new molecular-level understanding of the dynamic organization, in both time and space, of these critical protein complexes. This understanding could lead to the design of new treatments for learning and memory disorders. Furthermore, the research studies planned will provide current and future biomedical engineering students with the multidisciplinary training required to enter careers in the rapidly growing fields of biotechnology and biomedical engineering. Student skills will be enhanced by participation in cross-disciplinary engineering design teams, expanded interdisciplinary research opportunities for undergraduates and graduate students, and opportunities to engage in entrepreneurial activities. The proposed educational curriculum and outreach activities are expected to increase public awareness of the application of STEM disciplines to meet current national health needs.The project's objective is to quantitatively describe the spatiotemporal dynamics of protein signaling complexes that determine the strength of neuronal synaptic connections, which are mediated by two glutamate-gated ion channels (AMPAR receptors and NMDA receptors). The objective is driven by the rationale that elucidating the mechanisms of protein signaling complex formation and regulation is an important step toward identifying targets for pharmaceutical intervention in learning and memory disorders. The Research Plan is organized around 3 aims: 1) Experimentally measure protein-protein interaction dynamics of a large number of interacting proteins through literature mining and developing a new method to rapidly measure protein binding kinetics; 2) Construct computational models of NMDAR and AMPAR regulation to quantify the impact of various mechanisms on NMDA and AMPAR localization and identify parameters that need to be further characterized; 3) Quantitatively measure protein complex formation using labeling methods in conjunction with standard immune-labeling techniques to image protein complexes with single molecule localization super-resolution microscopy. The Educational Plan is organized around 2 aims: 1) Create a set of inquiry-based learning modules to teach fundamental principles of transport to K-12 students that will be presented to students in rural schools in Indiana and Ohio and the urban Purdue Polytechnic High School; 2) Create a multidisciplinary educational pathway for current and future Purdue students to obtain careers in fields of biomolecular detection, biotechnology, and technology development by designing and implementing new courses for undergraduate and graduate students that focus on biomolecular engineering and transport phenomena with special emphasis on the intersection of engineering, chemistry, and biology and developing expanded research and entrepreneurship activities that provide experiential learning opportunities that supplement skill attainment.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.