Many medical devices designed to address cardiovascular problems fail due to material-host interactions, in particular inflammation. Examples include artificial vascular grafts, stents, pacemaker leads, heart valves, and almost all other blood-contacting systems. These are examples of pathological cellular response to materials, but there is a material in our bodies that for the most part works well for decades. That material is the basement membrane which is a material made mostly of proteins to which vascular endothelial cells adhere in normal blood vessels. These endothelial cells receive cues from the basement membrane and their other surroundings that cause them to respond by not recruiting inflammatory cells or platelets except in pathological situations. What is it about this material that elicits desirable responses from endothelial cells whereas synthetic materials elicit undesirable responses? Can doctors use that knowledge to trick cells into responding to synthetic materials in a desirable way? To answer these questions, it is essential to understand how these cells sense their surroundings and convert those sensations into gene regulation. In this study we propose to systematically control the stiffness and protein composition of a material and then study the responses of human umbilical vein endothelial cells that are brought into contact with those materials. We will measure the activity of six or more molecules that transmit sensation from the cell's surface to its nucleus (each representative of a distinct signaling pathway) for cells in contact with materials of which we have varied stiffness and protein composition. To aid in interpretation of the data, we will use principal component analysis and partial least squares regression which are well-established techniques for making sense of highly complex, multivariate systems. Using these techniques we will correlate material properties with the signals that they activate. We hypothesize that unique material properties cause a unique pattern of cell signaling which in turn controls cellular production of molecules necessary for recruitment of inflammation. This hypothesis will be tested by completing three aims: (1) quantify signaling cascade activation when cells contact materials, (2) identify cell behaviors that result from these activated signaling cascades, and (3) study the role of signaling pathways via inhibitors of signaling molecules.
|Effective start/end date||07/01/2008 → 06/30/2011|