The goal of this K99/R00 program is to prepare my readiness in a research career and facilitate my transition from a post-doc fellow to an independent investigator position. To achieve this goal, I have developed (1) an original research proposal to continue pursuing the cutting-edge research in vascular bioengineering and (2) a career development plan to gain the knowledge and additional expertise that will contribute to the proposed study and beyond. I will receive rigorous training from a superb advisory committee consisting of five world- renowned experts including Drs. Shu Chien (primary mentor), Kun-Liang Guan, Shankar Subramaniam, Liangfang Zhang, and Ju Chen, at University of California San Diego, who will give me valuable advice and collaboration to accomplish the proposed research objectives. The focal nature of atherosclerotic lesions in disturbed flow regions suggests a regulatory mechanism acting on the endothelium by local hemodynamic environment. Recent reports suggest that YAP/TAZ, a transcription co-activator complex in controlling tissue growth and organ size, functions as a mechanosensor to mediate biophysical regulation of stem cell fate. However, it remains to be determined whether YAP/TAZ plays a role in modulating cardiovascular homeostasis and diseases. I recently discovered that the differential regulation of YAP/TAZ activity in vascular endothelial cells (ECs) by local flow patterns contributes significantly to the atheroprone endothelial phenotypes regarding proliferation and inflammation. My in vivo studies indicate that systemic inhibition of YAP/TAZ expression attenuates the disturbed flow-induced carotid atherosclerosis in Apolipoprotein E-null mice. Whether local inhibition of YAP/TAZ at atheroprone sites is sufficient to prevent/treat progression of atherosclerosis requires further investigation. My findings indicate that it is of prime importance to decipher the regulatory mechanisms of YAP/TAZ activation in mediating the atheroprone EC phenotypes, and to develop a therapeutic strategy based on YAP/TAZ inhibition at atheroprone sites. Our research team recently have developed the platelet-membrane cloaked nanoparticles (PNPs)-delivery system to target vascular injuries and atherosclerotic lesions. The PNPs will be a powerful vehicle for us to deliver YAP/TAZ inhibitors specifically to pre-existing plaques and examine YAP/TAZ as a therapeutic target in the progression of atherosclerosis. This research proposal tests the overall hypothesis that YAP/TAZ serves as a novel and important mechanotransducer in atherogenesis. The proposed studies will determine (1) the role of flow regulation of YAP/TAZ signaling pathway in vascular homeostasis and atherosclerosis, (2) the YAP/TAZ target genes that mediate the atheropro...