HFSP Research Grant

STRUCTURAL DAMAGE TO AXONS RESULTING FROM REPETITIVE MECHANICAL MOTION

The project aims to elucidate how repetitive mechanical motion damages internal structural components, such as microtubules, in axons of neurons and which repair mechanisms contribute to maintaining homeostasis. While traumatic brain injury models have revealed the structural damage by large stretching deformations of axons, the effects of subcritical stretching and bending repeated over thousands or millions of cycles have not yet been investigated. In engineering, fatigue and wear limit the lifetime of machines and devices due to accumulating microscopic damage of load-carrying parts. Clearly, cellular mechanisms for self-repair have evolved to support axonal functioning for over a century in some humans.
To identify both the damage mechanisms and the repair mechanisms whose balance maintains the structural and functional integrity of axons in the long term, we will study Dorsal Root Ganglion neurons which have a typical elongated axon, relatively high tensile strength and are involved in daily repetitive movement. Specifically, we will identify the repair mechanisms employed by the cell to mitigate and reverse the mechanical damage using imaging, transcriptomic and proteomic techniques.
Here we take an engineering perspective and apply it to cell biology by asking not “How does it work?” but “How does it keep working for so long?”. The obtained insights will inform our understanding of the mechanical aspects of homeostasis in cells, inspire new biomimetic approaches to engineering, and yield a better appreciation of the cell as
a “self-repairing machine”.

MAIN COLLABORATORS

Henry Hess, Columbia University, USA (Project Coordinator)

Orit Shefi, Bar-Ilan University, Israel

Akira, Kagugo, Hokkaido University, Japan