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: 10328492
• 负责人: Edward M Bahnson
• 金额: $ 15.44万
• 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/10328492
• 关键词: Address; Affect; Antiatherogenic; 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; 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; Knock-out; Knockout Mice; Laboratories; Lead; Location; Low Density Lipoprotein Receptor; Mediating; Medicine; Mentors; Modeling; Molecular Genetics; NanoGel; Nanotechnology; Oils; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Plant Roots; 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; base; 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; macrophage; 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，是麻省理工学院外科系的终身助理教授。我有一个 在氧化还原和血管生物学方面的扎实训练。我的博士后训练是在血管外科分部 在西北大学，我在转化研究和血管生物学方面获得了更多的经验。 虽然我有一个强大的基础，我需要更多的培训，以确保他的发展成为一个非常成功的 专注于血管疾病转化疗法的独立研究员。总的目标是 应用程序是通过指导和教学培训为我提供正是这些技能。具体来说，我会 专注于使用纳米技术和基于细胞介导的技术来提供基于氧化还原的治疗， 患病的脉管系统这个研究领域解决了我以前经验中的关键局限性。特别 细胞介导的传递领域和动脉粥样硬化模型。培训计划将使我们能够 新的高度新颖的翻译研究，这是至关重要的，因为我开始一个新的职业生涯作为助理教授在 外科学系。为了提供这种培训，我已经发展了一个全面的职业生涯， 发展和研究计划。我将由亚历山大卡巴诺夫教授指导，并由教授共同指导。 前田信代作为药物输送纳米技术中心主任，卡巴诺夫博士是一位专家， 纳米颗粒的设计和表征以及免疫细胞作为递送载体至 炎症前田信代博士是罗伯特·H。瓦格纳病理学杰出教授， 实验室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。除了她的专业技术外，前田博士还坚持认为， 对培养年轻科学家的巨大兴趣。为了促进他的进一步发展，我建立了一个 与Elena Batrakova博士合作，他在巨噬细胞和巨噬细胞衍生物方面拥有丰富的经验。 外泌体介导的药物递送。计划中的研究将结合纳米粒子的力量和创新 通过细胞介导的特异性靶向递送小分子药物。因为我已经证明了氧化还原 干预是血管保护模型的再狭窄，我建议使用氧化还原的方法， 用于治疗动脉粥样硬化的治疗剂。具体来说，我建议使用Nrf 2激活剂来影响 动脉粥样硬化动脉的氧化还原状态在炎症发作时就已局部出现。我已经证明， 将Nrf2激活剂肉桂醛直接应用于血管壁，激活Nrf2，减少细胞增殖， 增殖并降低氧化应激。这表明，Nrf 2激活剂的靶向给药是有效的。 血管保护和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 将药物封装在纳米颗粒（NP）中。我假设巨噬细胞会摄取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。