# Mechanical forces in nanoscale biology: From hemostasis to single-molecule centrifugation

> **NIH NIH R35** · BOSTON CHILDREN'S HOSPITAL · 2021 · $486,750

## Abstract

Abstract
Mechanical forces play key roles throughout biology, from governing the adhesion of leukocytes in the immune
response, to determining cell fate and directing tissue formation. This field of mechanobiology is providing vital
insights into conditions such as bleeding disorders, cancer, and infectious diseases, where it is becoming clear
that conventional biochemical and genomic characterizations are not sufficient to understand the rich behavior
of living systems or how they fail. Rather, we must uncover how force changes the structure and function of
molecules, triggering mechanotransduction pathways to modify cell responses. Technological developments
that enable precise manipulation of single molecules and cells have been a driving force in the development of
the field, but growth has been impeded by both limited access to such technologies and by constraints in their
capabilities, which has restricted the types of scientific questions that can be addressed.
To overcome these challenges, we will develop approaches in mechanobiology that will (i) open up new areas
of study through the introduction of new capabilities, and (ii) democratize single-molecule and nanoscale
methods so that all biomedical researchers can make discoveries using these powerful tools. We will continue
to develop instruments such as the Centrifuge Force Microscope, a miniature microscope that fits into a
benchtop centrifuge to enable even non-specialists to perform high-throughput single-molecule force
measurements, and nanoscale devices such as programmable DNA nanoswitches. We will develop DNA
nanoswitch calipers, a tool capable of measuring distances on single-molecules with angstrom-level precision
to enable single-molecule protein identification and shape determination. We will also develop Functional
Interaction-based Nanoswitch Discovery (FIND), a high-throughput screening assay based not on traditional
robotics, but on molecular devices that bring together molecular components to analyze and screen for
interactions of interest. FIND will enable screening of complex modes of action to find compounds that activate
a specific downstream pathway or allosterically stabilize a particular protein conformation.
We will apply our nanoscale approaches to answer key open questions in mechanobiology. For example, to
uncover the mechanical regulation of hemostasis we will use single-molecule methods to study the force-
regulated enzymatic cleavage of von Willebrand factor, and the flow-induced elongation and activation of its
adhesive function. We will also investigate the molecular basis of hearing and deafness by using single-
molecule force spectroscopy to probe the properties of the hair cell tip link, and combine this approach with
single-channel conductance measurements to simultaneously measure the force required to open
mechanotransduction channels and the molecular movements that underlie channel gating. Overall, these
efforts should firmly establish force as a...

## Key facts

- **NIH application ID:** 10167448
- **Project number:** 2R35GM119537-06
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Wesley Philip Wong
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,750
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167448

## Citation

> US National Institutes of Health, RePORTER application 10167448, Mechanical forces in nanoscale biology: From hemostasis to single-molecule centrifugation (2R35GM119537-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167448. Licensed CC0.

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