Grant: China-Canada Joint Health Research Initiative

Yang¿s group has established a transgenic line of mice expressing versican 3¿UTR. The hypothesis is that overexpression of versican 3¿UTR will bind and arrest endogenous miRNAs¿ functions. The inhibition of endogenous miRNA function frees the potential targets of these miRNAs. As a consequence, expression of these potential targets is promoted. With the assistance of Dr. Zhang¿s computational algorithms, Yang¿s group has then carefully examined the potential targets promoted by the transgenic expression of the versican 3¿UTR. It is found that Cathepsin B shares many miRNAs with versican 3¿UTR. Versican is an extracellular proteoglycan playing important roles in mediating cell activities associated with heart diseases and angiogenesis. Cathepsins are a group of enzymes playing roles in regulating ECM remodeling. We hypothesize that the 3¿UTR of vesicant serves as a competitor for miRNA binding, freeing other mRNAs from being repressed by the 3¿UTR-binding miRNAs. The microRNA miR-626 plays critical roles in mediating the functions of versican 3¿UTR. This application aims to investigate the regulatory effect of vesicant 3¿UTR on cathepsin-B functions mediated by miR-626. We will examine whether miRNAs modulate expression of versican and cathepsins and test their effects on endothelial cell migration and macrophage invasion. We will test the effects of miR-626 in regulating cell activities, tube-like structure formation associated with angiogenesis. The targeting interaction and regulation of expression and function of versican and cathepsin-B by miR-626 will be tested. Most importantly, we will analyze expression of cathepsin-B and other potential targets of miR-626 in the transgenic mice expressing vesicant 3¿UTR. We will perform wound healing assays and analyze new blood vessel formation in the wounded tissues. Potentially, this will increase the chance of survival and recovery in the patients with myocardial ischemia, and stroke.