Modulation of Signal Transduction by Nano-Topography

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DESCRIPTION: A fundamental question in cell biology is how surface topography regulates cell behavior. Our previous and ongoing work has focused on defining the topography of native basement membranes and determining the "phenotypic impact" of biologically relevant length scales on modulating corneal epithelial cell behaviors. Using silicon surfaces patterned with grooves and ridges, we have shown that biologic length scale topographic features modulate corneal epithelial cell orientation, adhesion, migration and proliferation. Topography also influences the architecture and orientation of focal adhesions as well as the distribution and orientation of cytoskeletal elements within the cell. Importantly, we have demonstrated that a transition in the cellular response to topography for many behaviors occurs at approx. 1,200 nm pitch (pitch = ridge + groove width) with the greatest impact of topography generally occurring in the nanoscale range, the range of feature sizes found in the native basement membrane. It is possible that the observed effects are caused directly (e.g. biomechanical transduction events initiated at the cell membrane) and/or indirectly (e.g. the topography of the substratum dictates the density and/or distribution of adhesion complexes which in turn modulate cell behaviors). Preliminary data support the central hypothesis that nanoscale (1-100 nm) and submicron (< 1 mu m) topographic features of the substratum, characteristic of those found in the native corneal basement membranes, constrain focal contact architecture resulting in altered signaling and cellular responses. These studies have relevance to our fundamental understanding of the role that topographic cues play in the normal development and maintenance of the corneal epithelium. Furthermore, data generated will contribute to the genesis of novel strategies in tissue engineering and advance the development of ocular prosthetics. We have assembled a strong interdisciplinary team of senior investigators to test the following hypotheses: Hypothesis 1: Integrins and syndecans mediate cellular responses to topographic cues. Hypothesis 2: The scale of topographic features modulates the activity of the Ras superfamily of GTPases. Hypothesis 3: The scale of topographic features modulates matrix receptor kinase targets that, in turn, modulate cell behaviors.