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.

抽象的 我，爱德华·巴恩森博士，是北卡罗来纳大学外科系的终身助理教授。我有一个 氧化还原和血管生物学方面的扎实培训。我在血管外科部门接受了博士后培训 在西北大学，我获得了转化研究和血管生物学方面的更多经验。 虽然我有很强的基础，但我需要更多的培训，以确保他发展成为一个非常成功的人 独立研究员，专注于血管疾病的转化疗法。本次活动的总体目标 应用程序的目的是通过指导和教学培训为我提供这些技能。具体来说，我将 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治疗方法 患病的脉管系统。这个研究领域解决了我之前经验中的主要局限性。特别 细胞介导的传递和动脉粥样硬化模型领域。培训计划将允许 mem 追求 新的高度新颖的转化研究对于我作为助理教授开始新的职业生涯至关重要 北卡罗来纳大学外科系。为了提供这种培训，我已经发展了全面的职业生涯 开发和研究计划。我将受到 Alexander Kabanov 教授的指导，并由 Alexander Kabanov 教授共同指导。 前田伸世.作为药物输送纳米技术中心主任，Kabanov 博士是以下领域的专家： 纳米颗粒的设计和表征以及使用免疫细胞作为递送载体至免疫位点 炎。 Nobuyo Maeda 博士是 Robert H. Wagner 病理学和病理学杰出教授 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。 第一个也是最强大的动脉粥样硬化模型。除了她的技术专长之外，前田博士还保持 对培养年轻科学家有着浓厚的兴趣。为了促进他的进一步发展，我建立了一个 与Elena Batrakova博士合作，她在巨噬细胞和巨噬细胞衍生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 干预措施在再狭窄模型中具有血管保护作用，我建议使用氧化还原方法作为 治疗动脉粥样硬化的治疗剂。具体来说，我建议使用 Nrf2 激活剂来影响 一旦炎症发生，动脉粥样硬化的局部氧化还原状态就会出现。我已经证明了 直接应用Nrf2激活剂肉桂醛，对血管壁激活Nrf2，减少细胞 增殖并减少氧化应激。这表明 Nrf 2 激活剂的靶向给药是 具有血管保护作用，可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，我会 将药物封装在纳米粒子 (NP) 中。我假设巨噬细胞会吸收 NP，定位到 动脉粥样硬化斑块，并提供基于氧化还原的治疗干预措施。

项目成果

Cannabis sativa extracts protect LDL from Cu2+-mediated oxidation.

大麻提取物可保护 LDL 免受 Cu2 介导的氧化。

• 发表时间: 2020
• 作者: Musetti, Bruno;González;González, Mercedes;Bahnson, Edward M;Varela, Javier;Thomson, Leonor
• 通讯作者: Thomson, Leonor

Cannabis sativa extracts protect LDL from Cu2+-mediated oxidation.

大麻提取物可保护 LDL 免受 Cu2 介导的氧化。

• 发表时间: 2020-10-15
• 作者: Musetti, Bruno;González;González, Mercedes;Bahnson, Edward M;Varela, Javier;Thomson, Leonor
• 通讯作者: Thomson, Leonor

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

使用急性免疫抑制疗法提高针对细胞内金黄色葡萄球菌的抗生素疗效。

• 发表时间: 2022-06-29
• 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

Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis.

氧化还原活性内体介导α5β1 整合素信号传导并促进骨关节炎中软骨细胞基质金属蛋白酶的产生。

• 发表时间: 2023-10-31
• 影响因子: 7.3
• 作者: Miao, Michael Z;Su, Qian Peter;Cui, Yang;Bahnson, Edward M;Li, Gang;Wang, Menglin;Yang, Yuchen;Collins, John A;Wu, Di;Gu, Qisheng;Chubinskaya, Susan;Diekman, Brian O;Yamada, Kenneth M;Loeser, Richard F
• 通讯作者: Loeser, Richard F