Engineering cell-based physiological monitoring devices
Abstract
In this project, we propose to develop a platform for engineering novel cell-based technology capable autonomously monitoring and co patients or warfighters to directly sense the presence of physiochemical inputs (e.g. hormones, metabolites, etc.) and rapidly respond to control physiological homeostasis by secreting a variety of physiomodulatory biomolecules, or report on physiological changes via MRI-detectable signals to wearable external devices. This technology could be used to monitor and treat chronic disease, act as sentinels for on-demand response to markers of physical or mecessary to implement this technology, demonstrate its design flexibility and quantitative performance, and compose and functionally validate device prototypes in vitro. This work will be highly interdisciplinary, involving protein engineering, synthetic biology, cell engineering, quantitative modeling, and biomaterials to construct and test the following engineered protein- and gene-based components: sensors (receptors), circuit wiring (engineered cellular signaling pathways, membrane channels, and genes) and actuators (secreted factors and MRI contrast agents). To accomplish our goals, we will leverage a recently developed signaling circuit engineering framework developed in our lab that uses a fast, post-translational mechanism (phosphorylation) to connect input signals (cell surface receptors) to outputs (secretion or MRI signal). Here, we will engineer circuits to accept inputs from diverse receptor types, demonstrating capabilities of circuits to broadly sense physiochemical space. Further, we will develop circuits capable of activating in the presence of two or more biomolecular cues, allowing for exquisite discrimination between different sets of biomolecular markers associated with specific physiological states. We will go on to engineer coupling between circuits and membrane channel activity, using aquaporin channel gating to create inducible contrast agents that can be read out by MRI in response to input detection, or affect circuit-induced fast-timescale secretion via Ca2+ influx and subsequent secretory granule release. Finally, we will construct and experimentally validate patient-deployable cell-based devices by porting our circuits to translationally relevant primary cells and encapsulate them in alginate. If successful, our work will deliver experimentally validated, quantitatively robust cell-based technology consistent with existing cell-based therapies and ready for in vivo animal studies. Additionally, our work will provide an engineering basis for broadly applicable cell-based technology that can directlybut not permanentlycouple to, report on, and actuate on a warfighters physiology, thereby enabling faster, more flexible, and higher precision performance than the current state of the art. Using this technology to understand how situational status affects physical condition and performance capabilities will be useful for variety of applications of interest to the Navy, including autonomous monitoring and entrainment of circadian rhythms to treat jet lag during long distance troop deployment. Other applications include tracking the progress of a soldier during training, assessing their operational readiness prior to a mission, providing real-time data on reaction to combat situations, and prioritizing medical attention after operations have concluded. Our proposal takes essential first steps toward this vision by establishing a robust engineering basis and creating benchmarked prototype devices that can be programmed to address a variety of physiological monitoring and control problems.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 06, 2021
- Source ID
- N000142114006
Entities
People
- Caleb J Bashor
Organizations
- Office of Naval Research
- Rice University
- United States Navy