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Testing Drug Targets for Atherosclerosis: Finding a Cure for Heart Attack

Dr Yung-Chih Chen, Institution: Baker Heart and Diabetes Institute

2018 Future Leader Fellowship

Years funded: 2019-2022


Myocardial infarction (MI) is the most frequent single cause of death. It is typically caused by rupture of atherosclerotic plaques in the coronary arteries and by subsequent thrombosis and vessel occlusion. Advances towards the understanding and prevention of plaque rupture have been hampered by the lack of an animal model that displays plaque instability and rupture as seen in humans. I have achieved major progress in establishing a unique mouse model of plaque instability/rupture that closely reflects human pathology. I am now using this mouse model, which is based on a specific tandem stenosis (TS) of the right carotid artery, to identify new molecular targets and drug candidates for plaque stabilisation. I will use proteomic and transcriptomic profiling comparing unstable, stable and healthy arteries.

Pilot proteomic data showed the potency of profiling in my TS model, identifying several proteins that are only or highly expressed in unstable plaques. Follow up on one of these newly described proteins, S100A8/9, showed a strong expression in mouse, as well as human unstable plaques. I also demonstrated that an inhibitor of these proteins achieved plaque stabilisation. I now propose to investigate further proteins identified in my profiling approaches. I will perform single cell RNA sequencing, thereby defining cell specific mRNA expression in vulnerable plaques. Also, in preliminary data I showed that diabetes causes an increase in plaque instability in the TS model, which is therefore also well suited for profiling towards mechanisms and targets for diabetes-associated plaque instability.

Finally, I will develop unstable plaque specific strategies using ROS- and pH-responsive nanoparticles as therapeutic vehicles, and CD40L ligand-selective Mac-1-blocking antibodies/peptides as therapeutic reagents. Overall, I will provide a better understanding of plaque vulnerability and develop novel and innovative plaque stabilising, selective and smart treatment options.

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