Classical theory has long held that the isometric force generated by airway smooth muscle (ASM) must be at every instant in a static mechanical equilibrium with the external load against which the muscle has shortened. In the previous grant period we established that this static picture does not apply in the setting of tidal loading as occurs during breathing, and must give way to the broader concept of the 'perturbed' contractile state that exists far from static equilibrium conditions. In this competing renewal application our central hypothesis is that the well-established static contractile state, the newly-elaborated perturbed contractile state, as well as the remarkable mechanical plasticity of ASM cells that has been reported recently by other laboratories and our own, are all subsumed under a rubric that is at once surprising, unifying and mechanistic. The specific hypothesis to be tested is that the ASM cell behaves as a glassy material. As we will explain, a glass is a material that has the disordered molecular state of a liquid and, at the same time, the rigidity of a solid. If true, then the ability of the ASM cytoskeleton to deform, to flow and to remodel would be determined by an effective temperature - called the noise temperature - representing the level of jostling (i.e., molecular noise or agitation) present in the intracellular microenvironment. The proposed research combines novel measurements of the contractile state with mathematical analysis of glassy behavior. The experimental method is to measure mechanical, biochemical and metabolic properties that characterize the contractile state at the levels of isolated tissues and cells in culture during specific interventions. The mathematical analysis is used to generate a series of 4 quantitative, mechanistic, testable predictions that follow directly from the hypothesis.
Aims 1 -4 will test these specific predictions while Aims 5 and 6 deal with logical extensions. Preliminary data support the feasibility of each aim. The abilities of the cytoskeleton to deform, to flow and to reorganize its internal structures represent basic biological processes that underlie a variety of higher cell functions. If supported by the data, therefore, this hypothesis might have implications in medicine and biology that go well beyond the immediate issues of smooth muscle shortening and its role in asthma.
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| Bursac, Predrag; Fabry, Ben; Trepat, Xavier et al. (2007) Cytoskeleton dynamics: fluctuations within the network. Biochem Biophys Res Commun 355:324-30 |
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