Macrophage-specific nanoparticles to understand atherosclerosis

巨噬细胞特异性纳米粒子用于了解动脉粥样硬化

• 批准号: 9274356
• 负责人: Sascha Nilu Goonewardena
• 金额: $ 16.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274356
• 关键词: ATP-Binding Cassette Transporters; Adenosine; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apoptosis; Arterial Fatty Streak; Arthritis; Asthma; Atherosclerosis; Autoimmune Diseases; Biological; Biology; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Chronic; Clinical; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Dendrimers; Deposition; Development; Disease; Dose; Fellowship; Foam Cells; Foundations; Functional disorder; Future; Generations; Genetic Techniques; Heart Diseases; Immune; Immunologics; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Institutes; Internal Medicine; Link; Lipoproteins; Liver X Receptor; Macrophage Activation; Malignant Neoplasms; Mediating; Medical; Medicine; Mentorship; Metabolism; Methotrexate; Michigan; Molecular; Molecular Genetics; Mus; Nanotechnology; National Heart, Lung, and Blood Institute; Natural Immunity; Observational Study; Pathology; Patients; Phase; Physicians; Production; Program Development; Property; Public Health; Purinergic P1 Receptors; Receptor Signaling; Research; Role; Science; Scientist; Signal Pathway; Strategic Planning; Testing; Therapeutic; Toxic effect; Training; Training Programs; Universities; Vascular Diseases; Work; atherogenesis; base; biological systems; cell type; chemical genetics; endothelial dysfunction; experience; faculty research; functional group; genetic approach; in vivo; macrophage; mouse model; nanoparticle; new therapeutic target; novel; personalized diagnostics; personalized therapeutic; physical property; preclinical study; professor; public health relevance; reverse cholesterol transport; scaffold; therapeutic target; tool

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：该提案描述了一个为期 5 年的培训计划，旨在培养心血管医学、纳米技术和免疫学方面的独立医师科学家。该候选人已完成心血管医学的临床培训，以及为期两年的纳米技术和免疫学博士后研究金。候选人将获得密歇根大学心血管医学主任、血管生物学领域公认的领导者 David J. Pinsky 博士的主要指导。共同指导将由博士提供。 Daniel Eitzman、Nick Lukacs 和 James R. Baker, Jr. Eitzman 博士是密歇根大学内科教授，在新陈代谢、炎症和动脉粥样硬化方面拥有丰富的经验。 Lukacs 博士是密歇根大学病理学教授兼研究学院助理院长，是先天免疫和巨噬细胞生物学领域的领导者。贝克博士是密歇根纳米技术生物与医学科学研究所所长，是免疫学和纳米技术领域的世界专家。动脉粥样硬化是冠状动脉疾病的最常见原因，是冠状动脉中脂蛋白沉积引起的内皮功能障碍和持续炎症的结果。据认为，动脉粥样硬化的进展 至少部分是由于巨噬细胞反向胆固醇转运 (RevCT) 功能障碍导致巨噬细胞凋亡和无法清除冠状动脉脂蛋白。尽管很清楚脂蛋白和巨噬细胞与动脉粥样硬化有关，但两者之间的关系以及巨噬细胞RevCT在动脉粥样硬化不同阶段的作用尚未明确。我的初步研究表明，甲氨蝶呤 (MTX) 会诱导巨噬细胞 RevCT，我可以将 MTX 连接到纳米颗粒支架上，并且我们可以在体外和体内将 MTX 递送至巨噬细胞。该提案的目的是确定 MTX 调节巨噬细胞 RevCT 的分子机制，并使用巨噬细胞特异性 MTX 纳米颗粒抑制体内动脉粥样硬化形成。我推测 MTX 会诱导巨噬细胞 RevCT，减弱巨噬细胞炎症反应并减缓动脉粥样硬化形成。该提案利用巨噬细胞特异性纳米粒子的力量，结合分子和遗传技术来定义 MTX 的抗动脉粥样硬化特性，以及巨噬细胞 RevCT 如何促进巨噬细胞极化和动脉粥样硬化。此外，该提案将为将这些新型纳米粒子应用于未来的研究奠定基础，以进一步了解血管疾病的免疫学基础，同时也为候选人在纳米技术、免疫学和血管生物学方面奠定坚实的基础。