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

细胞介导的靶向氧化还原干预治疗和预防动脉粥样硬化

• 批准号: 10534757
• 负责人: Edward M Bahnson
• 金额: $ 6.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534757
• 关键词: Address; Affect; Antiatherogenic; Aorta; ApoE knockout mouse; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Balloon Angioplasty; Biology; Blood Vessels; Bone Marrow; Bypass; Cardiovascular Diseases; Cell Proliferation; Cells; Cessation of life; Clinical; Coculture Techniques; Collaborations; Complex; Coronary; Cytoprotection; Development; Disease; Drug Delivery Systems; Encapsulated; Endarterectomy; Endothelial Cells; Ensure; Environment; Exocytosis; Folic Acid; Foundations; Functional disorder; Genetic; Glycolates; Goals; Harvest; Homeostasis; Hydrophobicity; Immune; Immune Targeting; Inflammation; Intervention; Kinetics; Knockout Mice; Laboratories; Location; Low Density Lipoprotein Receptor; Macrophage; Mediating; Medicine; Mentors; Modeling; Molecular Genetics; NanoGel; Nanotechnology; Oils; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Play; Polymers; Prevention; Procedures; Research; Research Personnel; Research Proposals; Role; Scientist; Shapes; Site; Smooth Muscle Myocytes; Solid; Stains; Stents; System; Technical Expertise; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Training; Translational Research; Universities; Vascular Diseases; Vascular Smooth Muscle; advanced disease; aortic arch; atheroprotective; career; career development; cinnamic aldehyde; crosslink; delivery vehicle; design; diabetic; direct application; distinguished professor; effectiveness testing; exosome; experience; folate-binding protein; in vivo; inflammatory milieu; innovation; interest; mouse model; nanocarrier; nanomedicine; nanoparticle; nanoparticle delivery; nanoscale; novel; post-doctoral training; prevent; professor; programs; recruit; research and development; restenosis; skills; small molecule; targeted delivery; targeted treatment; tenure track; translational impact; translational therapeutics; uptake; vascular inflammation

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.

摘要 我，爱德华·班森博士，是北卡罗来纳大学外科系的终身教职助理教授。我有一个 扎实的氧化还原和血管生物学方面的培训。我在血管外科接受了博士后培训 在西北大学，我在翻译研究和血管生物学方面获得了进一步的经验。 虽然我的基础很扎实，但我需要更多的培训，以确保他的发展成为一名非常成功的 专注于血管疾病的翻译疗法的独立研究人员。这个项目的总体目标是 应用程序就是通过有指导和说教的培训来为我提供这些技能。具体来说，我会 专注于使用纳米技术和细胞介导的技术来提供基于氧化还原的疗法 病变的血管系统。这个研究领域解决了我以前经验中的主要限制。尤其是 细胞介导的递送区域和动脉粥样硬化的模型。培训计划将使我能够继续 新的高度新颖的翻译研究对我开始新的职业生涯至关重要，我是一名 北卡罗来纳大学外科系。为了提供这种培训，我已经发展了一个全面的职业生涯 开发和研究计划。我将由亚历山大·卡巴诺夫教授指导，并由亚历山大·卡巴诺夫教授共同指导。 前田信代。作为药物输送纳米技术中心的主任，卡巴诺夫博士是 纳米颗粒的设计和表征以及免疫细胞作为载体输送到 发炎。前田信洋博士是罗伯特·H·瓦格纳的病理学和 检验医学。她是分子遗传学专家，也是apoE基因敲除小鼠的创造者 第一个也是最可靠的动脉粥样硬化模型。除了她的技术专长，前田博士还坚持认为 对培养年轻科学家的极大兴趣。为了进一步促进他的发展，我已经建立了一个 与埃琳娜·巴特拉科娃博士合作，后者在巨噬细胞和巨噬细胞方面拥有丰富的经验 外切体介导的药物传递。计划中的研究将把纳米颗粒的力量和创新结合在一起 小分子药物的输送，具有细胞介导性的特异性靶向。因为我已经证明了氧化还原 在再狭窄模型中，干预是血管保护的，我建议使用氧化还原方法作为 动脉粥样硬化治疗中的治疗剂。具体地说，我建议使用NRF2激活剂来影响 炎症发生时局部动脉粥样硬化动脉的氧化还原状态。我已经证明了 直接将Nrf2激活剂肉桂醛应用于血管壁激活Nrf2，减少细胞 促进细胞增殖，减少氧化应激。这表明，NRF2激活剂的靶向给药是 保护血管并将减少动脉粥样硬化中的氧化还原功能障碍。为了提供NRF2激活剂，我将 将药物包裹在纳米粒(NP)中。我假设巨噬细胞将摄取NP，定位于 动脉粥样硬化斑块，并提供基于氧化还原的治疗干预。

项目成果

The Use of Acute Immunosuppressive Therapy to Improve Antibiotic Efficacy against Intracellular Staphylococcus aureus.

• DOI: 10.1128/spectrum.00858-22
• 发表时间: 2022-06-29
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Beam, Jenna E.;Maiocchi, Sophie;Cartaya, Ana;Rowe, Sarah E.;Bahnson, Edward S. M.;Conlon, Brian P.
• 通讯作者: Conlon, Brian P.