Cell-Mediated Targeted Redox Intervention for the Treatment and Prevention of Atherosclerosis

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Abstract I, Dr. Edward Bahnson, am a tenure-track assistant professor at the Department of Surgery at UNC. I have a solid training in redox and vascular biology. I spent my post-doctoral training at the Vascular Surgery Divisions at Northwestern University, where I gained further experience in translational research, and vascular biology. Although I have a strong foundation, I require more training to ensure his development into a highly successful independent researcher focusing on translational therapies for vascular disease. The overall goal of this application is to provide me with precisely those skills through mentored and didactic training. Specifically, I will focus on using nanotechnology and cell-mediated-based technologies to deliver redox-based therapeutics to the diseased vasculature. This research area addresses key limitations in my previous experience. Particularly the area of cell-mediated delivery and models of atherosclerosis. The training plan will allow mem to pursue new highly novel translational research that is critical as I begin a new career as an Assistant Professor in the Department of Surgery at UNC. To provide this training, I have has developed a comprehensive career development and research plan. I will be mentored by Prof. Alexander Kabanov and co-mentored by Prof. Nobuyo Maeda. As Director of the Center for Nanotechnology in Drug Delivery, Dr. Kabanov an expert in nanoparticle design and characterization and the use of immune cells as delivery vehicles to sites of inflammation. Dr. Nobuyo Maeda is the Robert H. Wagner Distinguished Professor of Pathology and Laboratory Medicine. She is an expert in molecular genetics, and the creator of the apoE knockout mouse, the first and most robust model of atherosclerosis. In addition to her technical expertise, Dr. Maeda has maintained a vast interest in the training of young scientists. To facilitate his development further, I have established a collaboration with Dr. Elena Batrakova, who has extensive experience in macrophage and macrophage derive exosome-mediated drug delivery. The planned research will couple the power and innovation of nanoparticle delivery of small molecule drugs, with cell-mediated specific targeting. Since I have demonstrated that redox interventions are vasculoprotective in models of restenosis, I propose to use a redox approach as the therapeutic agent in the treatment of atherosclerosis. Specifically, I propose to use the Nrf2 activators to affect the redox status of atherosclerotic arteries locally early as soon as inflammation ensues. I have shown that direct application of the Nrf2 activator Cinnamic Aldehyde, to the vascular wall activates Nrf2, reduces cell proliferation and decreases oxidative stress. This suggests that targeted administration of Nrf 2 activators is vasculoprotective and will decrease redox dysfunction in atherosclerosis. To deliver Nrf2 activators, I will encapsulate the drugs in nanoparticles (NP). I hypothesize that macrophages will take up NP, localize to the atherosclerotic plaque, and deliver redox-based therapeutic interventions.