Accession Number:

AD1064084

Title:

Modular Extracellular Sensor Architecture for Engineering Mammalian Cell-Based Devices

Descriptive Note:

Journal Article - Open Access

Corporate Author:

Northwestern University Evanston Campus Evanston United States

Personal Author(s):

• Daringer, Nichole M.
• Dudek,Rachel M.
• Schwarz,Kelly A.
• Leonard,Joshua N.

Report Date:

2014-02-25

Pagination or Media Count:

13.0

Abstract:

Engineering mammalian cell-based devices that monitor and therapeutically modulate human physiology is a promising and emerging frontier in clinical synthetic biology. However, realizing this vision will require new technologies enabling engineered circuitry to sense and respond to physiologically relevant cues. No existing technology enables an engineered cell to sense exclusively extracellular ligands, including proteins and pathogens, without relying upon native cellular receptors or signal transduction pathways that may be subject to crosstalk with native cellular components. To address this need, we here report a technology we term a Modular Extracellular Sensor Architecture MESA. This self-contained receptor and signal transduction platform is maximally orthogonal to native cellular processes and comprises independent, tunable protein modules that enable performance optimization and straightforward engineering of novel MESA that recognize novel ligands. We demonstrate ligand-inducible activation of MESA signaling, optimization of receptor performance using design-based approaches, and generation of MESA biosensors that produce outputs in the form of either transcriptional regulation or transcription-independent reconstitution of enzymatic activity. This systematic, quantitative platform characterization provides a framework for engineering MESA to recognize novel ligands and for integrating these sensors into diverse mammalian synthetic biology applications.

Descriptors:

• biosensors
• cellular structures
• antigens
• proteins
• transcription factors
• amino acids
• chemical synthesis
• synthetic biology
• cell membrane
• cell engineering
• therapeutics
• immunotherapy
• regenerative medicine

Subject Categories:

• Anatomy and Physiology
• Genetic Engineering and Molecular Biology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE