Committee:

Michael Davis, Ph.D. (Georgia Institute of Technology & Emory University)

Charles Searles Jr., M.D. (Emory School of Medicine)                                                  

Loren Williams, Ph.D. (Georgia Institute of Technology)                                                   

Younan Xia, Ph.D. (Georgia Institute of Technology)                                                  

miR-744 Modulation by Disturbed Flow and Role in Endothelial Dysfunction and Atherosclerosis

 Atherosclerosis is the leading cause of death worldwide despite the use of cholesterol-lowering statins and anti-platelet drugs. The disease localizes to arterial regions exposed to disturbed flow due to the effect of low-magnitude and oscillating shear stress (OS) on endothelial gene expression. However, there are no treatment options to target hemodynamic-mediated mechanisms due to a lack of mechanistic understanding. The objective of this proposal is to elucidate the effects of d-flow-induced miRNAs on endothelial gene expression and the mechanisms initiating endothelial dysfunction and atherosclerosis. Recently, our lab reported that miR-663 is highly upregulated by OS in human endothelial cells and potentially induces endothelial inflammation. Interestingly, preliminary studies indicate that another miR-663 family member, miR-744, which has a common seed sequence with miR-663, is also upregulated by OS, and may also induce inflammation. Therefore, the overall hypothesis is that overexpression of miR-744 by OS causes endothelial dysfunction and atherosclerosis.  To test the hypothesis, miR-744 modulation of OS-induced endothelial dysfunction will be assessed in vitro, the therapeutic effect of miR-744 inhibition on atherosclerosis development will be assessed in vivo, and relevant direct targets will be determined.