The aim of our center will be to apply the tools of biology and nanoscience to control eukaryotic cell movement. During development, wound healing, or an immune response, cells must migrate to a specific location to interact with appropriate partner cells. Directed movement systems contain two essential subsystems: a guidance system that detects and processes external signals; and a force generating system that is engaged as output. Our center will use an engineering approach to elucidate the design principles of cellular motility systems -- we will attempt to design synthetic motility systems with reduced complexity and tunable parameters, This process should reveal the core requirements for such systems and will yield new nano-machinery that can be used to manipulate cell position and shape.
Our specific aims are to: 1. Generate a molecular toolkit of modular biological and artificial nano-components including ones that can detect signals, process information, and generate force. Components will be fabricated/modified so that they can be functionally linked to one another in diverse ways while avoiding excessive crosstalk with endogenous components. The toolkit will include hybrid (biological/artificial) nano-assemblies that utilize the distinct advantages of each class of material. 2. Apply the molecular toolkit to build synthetic motility systems/subsystems including: a) Synthetic guidance systems that can be inserted into living cells to direct actin based motiiity (e.g. in response to artificial ligand, light, etc.) b) Synthetic force generating systems based on actin-like polymers that can be regulated to drive motility c) Synthetic """"""""cells"""""""" (e.g.liposomes) with completely non-natural guidance and force generation systems that are capable of directed movement. The ability to control movement and targeting of cells could have revolutionary therapeutic potential. Immune cells with engineered motility systems could be programmed to target and destroy tumor cells. Engineered neuronal precursor cells could be guided to make precise connections to repair nerve function. Moreover, the toolkit that emerges from this center can be used to manipulate other complex cellular processes.
| Gordley, Russell M; Williams, Reid E; Bashor, Caleb J et al. (2016) Engineering dynamical control of cell fate switching using synthetic phospho-regulons. Proc Natl Acad Sci U S A 113:13528-13533 |
| Morsut, Leonardo; Roybal, Kole T; Xiong, Xin et al. (2016) Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors. Cell 164:780-91 |
| Maiuri, Paolo; Terriac, Emmanuel; Paul-Gilloteaux, Perrine et al. (2012) The first World Cell Race. Curr Biol 22:R673-5 |
| Moon, Tae Seok; Clarke, Elizabeth J; Groban, Eli S et al. (2011) Construction of a genetic multiplexer to toggle between chemosensory pathways in Escherichia coli. J Mol Biol 406:215-27 |
| Toettcher, Jared E; Voigt, Christopher A; Weiner, Orion D et al. (2011) The promise of optogenetics in cell biology: interrogating molecular circuits in space and time. Nat Methods 8:35-8 |
| Toettcher, Jared E; Gong, Delquin; Lim, Wendell A et al. (2011) Light-based feedback for controlling intracellular signaling dynamics. Nat Methods 8:837-9 |
| Tabor, Jeffrey J; Levskaya, Anselm; Voigt, Christopher A (2011) Multichromatic control of gene expression in Escherichia coli. J Mol Biol 405:315-24 |
| Lim, Wendell A; Pawson, Tony (2010) Phosphotyrosine signaling: evolving a new cellular communication system. Cell 142:661-7 |
| Tabor, Jeffrey J; Salis, Howard M; Simpson, Zachary Booth et al. (2009) A synthetic genetic edge detection program. Cell 137:1272-81 |
| Groban, Eli S; Clarke, Elizabeth J; Salis, Howard M et al. (2009) Kinetic buffering of cross talk between bacterial two-component sensors. J Mol Biol 390:380-93 |
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