This proposal describes a multi-disciplinary research program that aims to develop, validate, and disseminate microfluidic technologies for quantitative studies of protein aggregation and aging. Protein aggregation is associated with aging and with a number of human diseases that affect both quality and duration of life. Many fundamental aspects of protein aggregation remain elusive, including connections between protein aggregation and toxicity, and the connection between protein aggregation and initiation and progression of diseases. Microfluidic platforms will be developed to understand these complex processes from both bottom-up and top-down perspectives. Bottom-up, new droplet-based microfluidic systems will be developed to characterize quantitatively the connection between protein aggregation and toxicity in vitro. This system will allow the reproducible real-time generation, manipulation, and characterization of aggregates for in vitro and in vivo toxicity screens. Multidimensional statistical analysis of toxicity patterns obtained in these devices may elucidate the connection between protein aggregation and toxicity, clarify the mechanism of action of existing drug candidates that target aggregation, and accelerate development of new drugs and drug cocktails. Top-down, microfluidic technologies will be developed to induce and monitor aggregation in vivo with high spatiotemporal resolution, and to observe the effects of aging, physiological state, neuronal activity, and presence of drug candidates on the initiation and progression of protein aggregation diseases. These two technologies will be used together to understand protein aggregation and aging, and may lead to new hypothesis and molecules for controlling these processes.
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