# A synthetic signaling pathway engineering platform for creating precision cell-based sense-and-response devices

> **NIH NIH R01** · RICE UNIVERSITY · 2021 · $344,920

## Abstract

SUMMARY
Protein signaling networks are used by cells to sense, process, and respond to physical and molecular features
in their external environment. Engineering artificial signaling networks that couple membrane receptor-mediated
sensing of disease-associated signals to therapeutic responses could lead to breakthroughs in the development
of dynamic cell-based therapeutic devices capable of autonomously detecting and treating disease. In contrast
to native signaling networks, which rely on phosphorylation to transduce external signals, current approaches
for constructing synthetic signaling networks in humans rely on nonnative regulatory mechanisms and operate
on slow timescales or via single-turnover events. As a consequence, it is challenging to construct sense-and-
respond programs that accurately couple environmental fluctuations to output response, or that can flexibly in-
corporate diverse receptor-mediated inputs. The ability to engineer phosphorylation-based sense-and-response
programs could enable functional behavior resembling native pathways, including rapid detecting and integration
of extracellular signals. By enabling fine-tuned discrimination between different extracellular environments, such
programs could enhance safety and efficacy profiles of cell-based therapies. In this project, we will establish a
generalizable approach for engineering synthetic phosphorylation-based signaling in human cells, laying a foun-
dation for next-generation cell therapy devices capable of sensing molecular cues associated with disease, and
converting them into quantitatively defined therapeutic responses. To accomplish our goals, we will leverage a
synthetic biology platform recently developed by our lab that enables bottom-up construction of synthetic phos-
phorylation circuitry using engineered signaling proteins. As our preliminary work demonstrates, this platform
can be used to create synthetic signaling pathways connecting receptor-mediated detection of extracellular mol-
ecules to activation of downstream cellular processes (e.g., transcription). Here, we will investigate if this platform
can be used to engineer sense-and respond program to treat inflammatory disease. Specifically, we will: 1)
demonstrate the ability of synthetic pathways to be wired to receptors that sense diverse biomolecular cues
associated with inflammation; 2) engineer signaling networks that integrate multiple signals and respond exclu-
sively in the presence of defined combinations of inflammatory cues and; 3) test pathways in mesenchymal
stromal cells (MSCs) to assess translatability of our platform. Our work will illuminate foundational principles for
engineering synthetic signaling circuits and deliver a powerful technology platform for creating customized
sense-and-respond programs that can precisely distinguish between features of healthy and diseased tissue. In
addition to disease monitoring and diagnostic applications, these precision cell-based therapy devices ...

## Key facts

- **NIH application ID:** 10280787
- **Project number:** 1R01EB032272-01
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Caleb Bashor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,920
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280787

## Citation

> US National Institutes of Health, RePORTER application 10280787, A synthetic signaling pathway engineering platform for creating precision cell-based sense-and-response devices (1R01EB032272-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10280787. Licensed CC0.

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