Postdoc Fellowship for Tracy Smith PhD in Support of Mechanism and Targeting of the Host-Microbial Trimethylamine Pathway to Reduce Neointimal Hyperplasia after Injury

Cardiovascular disease is a leading cause of death globally. Despite advancements in surgical approaches for cardiovascular disease, up to 50% of vascular procedures such as balloon angioplasty, stenting, and surgical bypass fail due to recurrent narrowings (“restenosis”) and blockages from neointimal hyperplasia in the treated artery, thus representing an enormous clinical problem. Neointimal hyperplasia is a cellular proliferative and inflammatory process similar to an overexuberant wound healing response after injury that results in harmful scaring in the treated segment of the artery. Our goal is to develop novel therapies for preventing and treating neointimal hyperplasia after vascular surgery. However, there are major gaps in knowledge about how genetic and environmental factors interact to cause inter-individual variability in susceptibility to this condition. We propose a novel pathway for neointimal hyperplasia that links bacteria living in the gut (“microbiota”), a biologically active small molecule (“metabolite”) called trimethylamine N-oxide (TMAO) produced by gut microbiota from dietary nutrients, and neointimal hyperplasia after vascular surgery. We propose a series of experiments that will test phenomenological, mechanistic, and translational aspects of this pathway, thus having the potential for transformative biologic discovery and impact on patients undergoing vascular surgery.