I. OVERALL Lead PI: Wendell Lim Exploring Design Principles of Cellular Control Circuits SUMMARY The UCSF Center for Systems and Synthetic Biology is focused on the fundamental question of how cells make decisions using genetically encoded molecular networks. Our philosophy is to use a combination of network engineering, analysis, and modeling to comprehensively understand the underlying algorithmic principles that cells use to make regulatory decisions. Our Center is therefore focused on developing new synthetic biology tools for network perturbation and rewiring, as well as quantitative, single-cell approaches for analyzing how such changes alter cellular behavior. Together such tools will allow us to better map genotype- phenotype relationships that control both dynamic and spatial responses in cells. For the second funding period, our Center is focusing much of its innovative effort on trying to apply our understanding of cell decision- making to medicine: our most forward-looking aim is to use synthetic biology approaches to engineer cells that could be used as therapeutics, including immune cells and stem cells with customized user-defined response behaviors. Designer therapeutic cells provide the ultimate testbed for our understanding of cellular logic. More broadly, the Center aims to play a leadership and catalytic role in the development of this transformative field, both at our own institution and within the national and international scientific and educational community.
The cells in our body must constantly make complex decisions. We currently lack a complete understanding of how the molecules in our cells can act as a coherent system to make such decisions. To approach this problem, we are using a combination of theory and engineering-inspired experimental approaches to try to understand the design logic of cellular decision-making networks. These approaches should lead to a deeper and more quantitative understanding of how cellular circuits function. They should thus give us a better predictive understanding of how defects in these circuits lead to disease, and how we might combat these perturbations to restore proper function. We also hope to gain a better understanding of how we might engineer cells as therapeutic agents.
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|Aranda-Díaz, Andrés; Mace, Kieran; Zuleta, Ignacio et al. (2017) Robust Synthetic Circuits for Two-Dimensional Control of Gene Expression in Yeast. ACS Synth Biol 6:545-554|
|Lim, Wendell A; June, Carl H (2017) The Principles of Engineering Immune Cells to Treat Cancer. Cell 168:724-740|
|Nissen, Kelly E; Homer, Christina M; Ryan, Colm J et al. (2017) The histone variant H2A.Z promotes splicing of weak introns. Genes Dev 31:688-701|
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|Wilson, Maxwell Z; Ravindran, Pavithran T; Lim, Wendell A et al. (2017) Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Mol Cell 67:757-769.e5|
|Datta, Anirban; Sandilands, Emma; Mostov, Keith E et al. (2017) Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cell Signal 40:91-98|
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