The long term objective of the proposed work is to understand the structural/mechanical basis of cell shape and the cytomechanical role of the cytoskeleton. Understanding the mechanical basis for cell shape and function is important because of rapidly accumulating evidence that mechanical force is a """"""""second messenger"""""""" capable of regulating differentiation, morphogenesis, macromolecular synthesis, ion currents and other aspects of cellular physiology. This proposal focusses on the role of tension as an information source regulating axonal growth and retraction. Putting this in terms of more familiar chemical paradigms, we investigate tension as """"""""second messenger"""""""" regulating neural axon development. Our working hypothesis is a general regulatory schema for tensile control of neurite length, a 3 position controller (like a double pole, double throw electric switch). Neurites respond to the continuum of tensions; high tension levels cause growth, the """"""""forward"""""""" position of the switch. Tensions near the resting level elicit passive (non-growing) viscoelastic neurite response, the """"""""neutral"""""""" switch position. Low tensions cause neurite tension production and retraction, the """"""""reverse"""""""" switch position. Informed by this general control scheme, we propose to examine cell physiological effects of different levels of the tension messenger, the cellular source of this messenger and the output of """"""""second messenger"""""""" under different physiological conditions. The methodology used for these experiments are quantitative measurements and applications of tension by glass needles. Because these methods are quantitative, the experiments proposed here also provide a functional assay, heretofore lacking, to investigate specific, poorly understood aspects of neuronal growth: the relationship of growth cone behavior to forward motility; the regulation of neurite elongation rate by the substrate; and the role of tension in neurite initiation. The health relatedness of this basic research lies its illumination of tension as a poorly understood, but apparently general, regulator of cell physiology and development.
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