# Programming cellular behavior by mechanical forces

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $1,508,357

## Abstract

ABSTRACT
Cellular behaviors are modulated by a variety of stimuli in the environment, which can be generally categorized
as chemical, physical, and biological factors. Previous work suggests that physical forces, both at the mesoscale
of cell-cell interactions and the microscale of ligand-receptor binding events, play a critical role in regulating cell
physiology. For example, stem-cell differentiation is regulated by neighboring cells and the stiffness of the
extracellular matrix, while T cells are better activated by target cells with a mechanically strong cortex. The T-
cell receptor also bears forces exerted from the pMHC, which affects receptor activation in a non-monotonic
manner. While a plethora of evidence suggests the critical role of mechanical force in regulating cell fate and
activation states, force itself has rarely been considered or exploited as a target for cell engineering and
therapeutics development. Major hurdles include the lack of effective sensors that can digitally sense mechanical
forces, and the lack of genetically encoded intracellular devices that can convert mechanical forces into a
signaling cascade that modulates cell states. In this proposal, we will combine state-of-the-art technologies in
protein design, RNA synthetic biology, and cell engineering to develop “mechaswitches”: universal, modular and
programmable signal transduction systems that are able to trigger specific cellular actions in response to
mechanical signals. Each mechaswitch is composed of a protein-based force sensor inserted within a force-
bearing protein of interest and a transducer mRNA that implements a desired cellular action. When the protein
of interest is subjected to a defined range of forces, the mechaswitch force sensor responds by changing its
conformation. This conformational change is in turn detected by a sensing element within the transducer mRNA
that either switches on or off the expression of specific proteins that modulate cell behavior. We will develop
sensors covering a wide range of molecular forces and RNA switches that control protein expression with high
fidelity. In proof-of-principle experiments, we will apply mechaswitches to program cell differentiation in defined
extracellular environments and to modulate T cell proliferation and activation in response to specific antigens.
Because of the modularity of mechaswitches, which enables their sensing and output components to be rapidly
swapped and recombined, we envision a host of other uses for mechaswitches that could transform the study
and application of mechanical forces in cell biology. The successful realization of this project is expected to not
only advance basic research in mechanobiology, but also lay the foundation for the first therapeutic strategies
informed by the mechanical signals and target mechano-properties of diseased cells and proteins.

## Key facts

- **NIH application ID:** 10917785
- **Project number:** 1R01EB037112-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Julien Berro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,508,357
- **Award type:** 1
- **Project period:** 2024-09-09 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917785

## Citation

> US National Institutes of Health, RePORTER application 10917785, Programming cellular behavior by mechanical forces (1R01EB037112-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10917785. Licensed CC0.

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