This proposal describes a 5-year training program for the development of an independent, physician scientist in cardiovascular medicine, nanotechnology, and immunology. The candidate has completed clinical training in Cardiovascular Medicine, as well as a two-year postdoctoral fellowship in nanotechnology and immunology. The candidate will receive primary mentorship from Dr. David J. Pinsky, Chief of Cardiovascular Medicine at the University of Michigan and a recognized leader in vascular biology. Co-mentorship will be provided by Drs. Daniel Eitzman, Nick Lukacs, and James R. Baker, Jr. Dr. Eitzman is a Professor of Internal Medicine at the University of Michigan with extensive experience in metabolism, inflammation, and atherosclerosis. Dr. Lukacs is a Professor of Pathology and Assistant Dean for Research Faculty at the University of Michigan who is a leader in innate immunity and macrophage biology. Dr. Baker, the director of the Michigan Nanotechnology Institute for Biology and Medical Sciences, is a world expert in immunology and nanotechnology. Atherosclerosis, the most common cause of coronary artery disease, is the consequence of endothelial dysfunction and persistent inflammation driven by lipoprotein deposition in the coronary arteries. It is believed that progression of atherosclerosis is at least partly due to dysfunction in macrophage reverse cholesterol transport (RevCT) that leads to macrophage apoptosis and an inability to clear coronary lipoproteins. Although it is clear that lipoproteins and macrophages are associated with atherosclerosis, the relationship between the two and the role of macrophage RevCT in different phases of atherogenesis has not yet been defined. My preliminary studies demonstrate that methotrexate (MTX) induces macrophage RevCT, that I can attach MTX to a nanoparticle scaffold, and that we can deliver MTX to macrophages in vitro and in vivo. The objective of this proposal is to define the molecular mechanisms through which MTX regulates macrophage RevCT and to use the macrophage-specific MTX nanoparticles to inhibit atherogenesis in vivo. I hypothesize that MTX induces macrophage RevCT, blunting in macrophage inflammatory responses and slowing atherogenesis. This proposal leverages the power of macrophage-specific nanoparticles in combination with molecular and genetic techniques to define the anti-atherogenic properties of MTX and how macrophage RevCT contributes macrophage polarization and atherosclerosis. Furthermore, this proposal will lay the groundwork to apply these novel nanoparticles towards future studies to further understand the immunologic basis of vascular disease while also providing the candidate with a strong foundation in nanotechnology, immunology, and vascular biology.
The proposed research is relevant to public health because the development of cell- specific therapeutics for heart diseases will help us to understand the molecular drivers of these diseases and to develop personalized diagnostic and therapeutic tools for patients with heart disease. The proposed research is relevant to the NHLBI's strategic plan in that it focuses on moving scientific discovery from 'form to function,' 'function to causes,' and 'causes to cures.'
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