The end-effector of acute airway narrowing is the airway smooth muscle (ASM) cell. The ASM cell has a cytoskeleton that is in a continuous state of remodeling, and this remodeling is now thought to be a major factor contributing to the excessive airway narrowing that is a cardinal feature of asthma. To explain the extent of this remodeling and its rate of progression, here we offer a novel mechanistic hypothesis. CSK remodeling proceeds at a rate that varies dramatically; depending upon circumstances, in the same muscle it can be completed on time scales as short as days, hours, or even minutes. We have argued in recent publications that the extent of smooth muscle remodeling, the rate at which it progresses, and the mechanisms that drive it, all appear to fit within the framework of molecular trapping in deep energy wells and molecular hopping out of those wells driven by an effective matrix temperature. This framework is simple, attractive, and fits all published observations; for example, the panels below illustrate at the tissue level that the ASM strip does indeed remodel more and remodel faster while the matrix is """"""""hotter"""""""" (i.e., higher x). But the arguments in favor of this framework and its plausibility have been entirely post hoc; without exception the supporting evidence has been circumstantial and correlative. This research is designed to provide the mechanistic basis that would support or refute the tenability of that framework. The hypothesis predicts the existence of: intermittent nano-scale hopping transitions from one metastable state to another; extremely slowly evolution of the CSK into more stable microconfigurations (physical aging); resetting of that evolution by imposed mechanical stresses that are large enough to overcome energy barriers and bring the system to a new microconfiguration (rejuvenation).
Aim 1 focuses on the cellular level; it is designed to test the existence of aging and rejuvenation in cells subjected to physiological mechanical loading.
Aim 2 focuses on the molecular level; it is designed to test the existence of molecular- scale hops and to characterize the molecular forces that drive those hops.
Aim 3 integrates these levels; it is designed to link together aging, rejuvenation, and hopping; it proposes to establish that those structures that age and rejuvenate are the very same ones that remodel by hopping. Lay summary: The ability of the cell to rearrange the molecules of its internal skeleton plays an important role in airway narrowing in asthma, vessel narrowing in vascular disease, and cell invasion in cancer. Here we investigate a different way of understanding how this basic rearrangement process might work. ? ? ?
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| Trepat, Xavier; Fabry, Ben; Fredberg, Jeffrey J (2010) Pulling it together in three dimensions. Nat Methods 7:963-5 |
| Angelini, Thomas E; Hannezo, Edouard; Trepat, Xavier et al. (2010) Cell migration driven by cooperative substrate deformation patterns. Phys Rev Lett 104:168104 |
| Oliver, Madavi; Kováts, Tímea; Mijailovich, Srboljub M et al. (2010) Remodeling of integrated contractile tissues and its dependence on strain-rate amplitude. Phys Rev Lett 105:158102 |
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