Modular Extracellular Sensors for Cell-based Biosensors
- 技术优势
- Enhanced signal to noise ratioNot susceptible to native regulatory mechanisms
- 详细技术说明
- Engineered receptors designed to control gene expression #biosensor#detection #diagnostics #therapeutics #cellsignalling
- *Abstract
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Engineering mammalian cell-baseddevices that monitor and therapeutically modulate human physiology is apromising and emerging frontier in clinical synthetic biology. However,realizing this vision required new technologies enabling engineered circuitryto sense and respond to physiologically relevant cues. Currently, no existingtechnology enables an engineered cell to sense exclusively extracellularligands, including proteins and pathogens, without relying upon native cellularreceptors or signal transduction pathways that may be subject to crosstalk withnative cellular components. Northwestern researchershave developed a platform technology of living cell-based biosensors namedModular Extracellular Sensor Architecture (MESA). They designed and engineeredmodular receptors as a means to control intracellular gene expression. In thistechnology, they created MESA receptors to form heterodimeric structures uponextracellular ligand binding. The proximity of the intracellular regions allowsa protease chain of one structure to cleave and release a transcription factorin the other, which then induces gene expression in the nucleus. Theresearchers have iteratively improved MESA receptor designs for improvedperformance characteristics and achieved simultaneous reduction in backgroundand enhancement of the signal-to-noise ratio. This sensing modality is novel inthat it does not require the use of any native protein-protein interactions forsignal transduction, i.e. it can be fully orthogonal, and thus is notsusceptible to native regulatory mechanisms. They demonstratedligand-inducible activation of MESA signaling, optimization of receptorperformance using design-based approaches, and generation of MESA biosensorsthat produce outputs in the form of either transcriptional regulation ortranscription-independent reconstitution of enzymatic activity. Thissystematic, quantitative platform characterization provides a framework forengineering MESA to recognize novel ligands and for integrating these sensorsinto diverse mammalian synthetic biology applications.
- *Inventors
- Joshua Leonard* Rachel Dudek Nichole Daringer
- *Publications
- Daringer N, Dudek R,Schwarz K and Leonard J (2014) Modular Extracellular Sensor Architecture forEngineering Mammalian Cell-based Devices. ACS Synthetic Biology, 3: 892-902.
- 国家/地区
- 美国
