DESCRIPTION (provided by applicant): Karen J. Ho's career goals are to become an independently-funded, academic vascular surgeon- scientist, advance the field of vascular surgery, and specifically reduce the burden of restenosis after interventions such as angioplasty/stenting and bypass surgery. She has a sound foundation for achieving these objectives through her undergraduate studies in molecular biophysics and biochemistry at Yale, medical training at Harvard, surgical and vascular training at Brigham and Women's Hospital, and postdoctoral research training at Brigham and Women's Hospital and Beth Israel Deaconess Hospital. Now at Northwestern University, her role is to develop a basic science research program in vascular surgery, and she has unconditional support from her Department and mentors. She also has the drive and intellect to develop a research direction in the microbiome that is new to her but which is exciting, innovative, and novel. Dr. Ho's immediate goal is to use the protected research time and mentorship structure of the K08 Award to enhance her knowledge and scientific research skills in the gut microbiome to effectively study the mechanism by which gut microbes and microbe-derived metabolites regulate neointimal hyperplasia, with the eventual goal of developing complementary or alternative dietary strategies that modulate the microbiome to reduce the risk of restenosis after arterial interventions. Atherosclerosis will continue to be a major public health problem in the foreseeable future due to the increasing prevalence of obesity, hypertension, and diabetes. Furthermore, restenosis as a cause of failure of interventions for atherosclerosis continues to be an intractable problem despite decades of research, underscoring the importance of a novel approach. Although we have a symbiotic relationship with our gut microbiota, perturbations that alter the quantity or makeup of gut microbes have been linked to chronic inflammatory diseases including obesity, diabetes, atherosclerosis, and inflammatory bowel disease. In certain cases, this relationship may involve gut microbe- derived metabolites such as short chain fatty acids (SCFA), which are produced by microbial fermentation of dietary fiber. Dr. Ho's preliminary work over the past year and a half shows that inbred rats treated with antibiotics have exacerbated neointimal hyperplasia after carotid angioplasty, an effect that is reversed by concomitant supplementation with sodium butyrate, a major SCFA. Furthermore, butyrate has an anti- proliferative and anti-migratory effect in vascular smooth muscle cells in vitro. Thus, we hypothesize that gut microbiota influence the arterial injury response through the production of SCFA. To investigate this hypothesis, the aims of this proposal are (1) to evaluate the functional role of the gut microbiome in a murine model of neointimal hyperplasia, (2) to determine if microbiome-derived SCFA regulate neointimal hyperplasia through...