Research in genomics and proteomics is constantly identifying -- by qualitative screening -- thousands of new molecules of proteins, DNA and RNA critical to health or responsible for a disease. Detailed understanding of the structure and function of these molecules is of fundamental importance to biology and medicine, but it is difficult to achieve by traditional methods, which are labor intensive and consume large amounts of samples. Microfluidics allows manipulations and monitoring of minute volumes of solutions, and is attractive as the key technology for overcoming limitations of traditional methods. However, microfluidic devices have not yet found widespread applications as research tools. An intense research effort is directed towards solving three problems of microfluidics: i) large dispersion of solution along the channels increases consumption of reagents and also makes long (minutes to days) time scales difficult to access; ii) slow mixing of solutions makes very short (tens of milliseconds and below) time scales inaccessible; mixing approaches that rely on turbulence prohibitively increase the sample consumption; iii) chemistry of internal surfaces of devices is important and has to be controlled. This multi-disciplinary program will begin by developing a new microfluidic technology that is universal -- it will be useful for quantitative, high-throughput experiments on time scales ranging from tens of microseconds to days. Dispersion will be eliminated by localizing reagents inside aqueous droplets encapsulated by an immiscible fluid. Mixing inside the droplets will be accelerated by using chaotic advection, rather than turbulence. Surface chemistry to which solutions are exposed will be controlled by careful choice of surfactants. This program will then demonstrate the utility of this technology for biomolecular functional and structural studies. It will be used as the basis for unique kinetics systems suitable for measurements of dynamics on time scales from tens of microseconds to seconds. This kinetics system will be applied to measurements of fast enzyme kinetics and early events in RNA folding. This technology will also be used for protein crystallization to control both short time scale events such as nucleation, and to control long time scale events such as growth. Finally, the program will develop methods for making these technologies user-friendly and implement them in laboratories of our collaborators. This technology will improve health by enabling basic research. It will not only enable measurements and experiments that are impossible to do today; it will also make these measurements rapid, economical, and accessible to a wide community of researchers in biology, biophysics, and bioengineering.
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