Mechanical stimuli regulate many cellular responses, particularly within the cardiovascular system. Understanding the process of mechanotransduction has been challenging, in part because techniques for precisely controlled mechanical stimulation have not been widely used. We proposed that rigorous, highly specific and controllable methods of studying mechanotransduction are needed. By combining the sensitive reporting, we have developed a powerful system for studying mechanotransduction. We have identified several novel genes that are highly mechanoresponsive in human aortic smooth muscle cells. By cloning functional promoters for these genes 5' to the beta-lactamase reporter gene, we have created a powerful specific molecular assay for gene induction in living cells. We will perform mechanical stimulation of cells using magnetic force and follow specific promoter responses using two-photon 3D microscopy. Thus, this experimental system will permit the study of specific molecular responses by precisely controlled mechanostimulation. The specific hypotheses to be tested are highly relevant to a number of cardiovascular diseases, including hypertensive vasculopathy. However, we believe that the lessons from these studies will extend beyond the vascular smooth muscle cell and provide insight into tissue engineering principles.
Aim 1) We will explore characteristics of the mechanical stimulus necessary to induce a molecular response.
Aim 2) We will explore the role of mechanotransduction through specific integrin subunits in the molecular mechanoresponses of vascular smooth muscle cells.
Aim 3) We will explore the relationship between the nature of the mechanical stimulus required to induce one gene may be greater than the stimulus required to induce another gene.
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