ThegoalofthisK99/R00programistopreparemyreadinessinaresearchcareerandfacilitatemytransition from a post-doc fellow to an independent investigator position. To achieve this goal, I have developed (1) an originalresearchproposaltocontinuepursuingthecutting-edgeresearchinvascularbioengineeringand(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 collaborationtoaccomplishtheproposedresearchobjectives. Thefocalnatureofatheroscleroticlesionsindisturbedflowregionssuggestsaregulatorymechanismacting ontheendotheliumbylocalhemodynamicenvironment.RecentreportssuggestthatYAP/TAZ,atranscription co-activator complex in controlling tissue growth and organ size, functions as a mechanosensor to mediate biophysicalregulationofstemcellfate.However,itremainstobedeterminedwhetherYAP/TAZplaysarolein 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 ApolipoproteinE-nullmice.WhetherlocalinhibitionofYAP/TAZatatheropronesitesissufficienttoprevent/treat progressionofatherosclerosisrequiresfurtherinvestigation.Myfindingsindicatethatitisofprimeimportance todeciphertheregulatorymechanismsofYAP/TAZactivationinmediatingtheatheroproneECphenotypes,and todevelopatherapeuticstrategybasedonYAP/TAZinhibitionatatheropronesites.Ourresearchteamrecently havedevelopedtheplatelet-membranecloakednanoparticles(PNPs)-deliverysystemtotargetvascularinjuries andatheroscleroticlesions.ThePNPswillbeapowerfulvehicleforustodeliverYAP/TAZinhibitorsspecifically topre-existingplaquesandexamineYAP/TAZasatherapeutictargetintheprogressionofatherosclerosis.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/TAZsignalingpathwayinvascularhomeostasisandatherosclerosis,(2)theYAP/TAZtargetgenesthat mediate the atheroprone EC phenotypes, and (3) lesion-targeted YAP/TAZ inhibition as a novel therapeutic strategytoprevent/treatatherosclerosis.Thisworkwillincreaseourunderstandingofthemechanismsbywhich disturbed flow mediates atherorprone phenotypes and lesion progression, as well as contributing to novel approachesforatherosclerosispreventionand/ortreatment.
Atherosclerosis, the most common cause of acute myocardial infarction, ischemic stroke, and peripheral vasculardiseases,resultsfromendothelialdysfunctionandmaladaptiveinflammationinthearterialwall.The objectives of this proposed study are to (1) elucidate a novel mechanism by which local hemodynamics regulates the activities of two novel transcription co-activators YAP/TAZ to modulate endothelial phenotypes and atherogenesis, and (2) develop anti-YAP/TAZ nanomedicine for treatment/prevention of atherosclerosis. The knowledge gained from this research project will advance our understanding of pathogenesis of atherosclerosisandthedevelopmentofnoveltherapeuticstrategies.
