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 modulation of systemic and/or local inflammation, and (3) to determine if microbiome-derived SCFA regulate neointimal hyperplasia through direct modulation of cellular proliferation, migration, and/or apoptosis. The scientific environment at Northwestern University and the University of Chicago, the mentorship team and multidisciplinary Advisory Committee, and the proposed Career Development Plan are centered around Dr. Ho's objective to use protected time to enrich her working knowledge of characterizing and manipulating the microbiome and applying these to the pathogenesis of neointimal hyperplasia. Northwestern University's Feinberg Cardiovascular Research Institute is Dr. Ho's principal location for this proposal. Dr. Melina Kibbe is Dr. Ho's primary mentor and an experienced physician-scientist in the Department of Surgery at Northwestern University. Dr. Kibbe's laboratory has expertise in animal models of neointimal hyperplasia and atherosclerosis and in vascular biology. Dr. Ho's lab in Feinberg Cardiovascular Research Institute is located in close proximity to Dr. Kibbe's and she has access to multiple Northwestern University core facilities, an animal facility, and advisors in scientific research. The University of Chicago's Biological Sciences Division Section of Gastroenterology is a second site for this proposal. Dr. Eugene B. Chang, Dr. Ho's co-mentor, is a seasoned investigator at the University of Chicago in the gut microbiome and host-microbial interactions. His research specializes in intestinal epithelial, biology/pathobiology, cultivation-dependent and cultivation-independent approaches to studying gut microbiota, and mucosal immunology. His lab in the state-of-the-art Knapp Center for Biomedical Discovery includes the NIDDK P30 Digestive Diseases Research Core Center and is only 20 minutes away by car from the Northwestern University Chicago campus. During the award period, Dr. Ho will elect formal coursework at both sites. This proposal and the assembled environmental and mentoring support plan address dual purposes: to advance Dr. Ho's scientific skills through a structured mentorship and protected scientific framework and to determine the mechanistic role of the gut microbiome in neointimal hyperplasia. The unwavering support of both Northwestern University and University of Chicago to Dr. Ho to meet these objectives will provide her with the skills necessary to achieve her goal of becoming an independent surgeon scientist.

Public Health Relevance

Blockages in blood vessels caused by advanced atherosclerosis frequently lead to heart attacks, strokes, foot ulcers, gangrene, and limb loss and can be treated by balloon angioplasty/stenting and bypass surgery. However, the rate of treatment failure due to 'restenosis,' or recurrent narrowing of arteries due to excessive thickening and scarring of the vessel wall, can reach 50% in 5 years. In this research program, we will investigate the mechanisms by which short chain fatty acids and other gut microbe-derived metabolites regulate the healing response of blood vessels and whether strategies for changing the composition and activity of gut microbes can reduce the risk of restenosis after cardiovascular interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
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Lidman, Karin Fredriksson
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Northwestern University at Chicago
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United States
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Cason, Cori A; Dolan, Kyle T; Sharma, Gaurav et al. (2018) Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J Vasc Surg 68:1552-1562.e7
Chen, Edmund B; Cason, Cori; Gilbert, Jack A et al. (2018) Current State of Knowledge on Implications of Gut Microbiome for Surgical Conditions. J Gastrointest Surg 22:1112-1123
Ho, Karen J; Varga, John (2017) Early-Life Gut Dysbiosis: A Driver of Later-Life Fibrosis? J Invest Dermatol 137:2253-2255