Macrophage-specific nanoparticles to understand atherosclerosis

 描述(由申请人提供)：本提案描述了一项为期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内科科学家。该候选人已经完成了心血管医学的临床培训，以及纳米技术和免疫学的两年博士后奖学金。候选人将接受密歇根大学心血管内科主任、公认的血管生物学领袖大卫·J·平斯基博士的初级指导。共同导师将由Daniel Eitzman博士、Nick Lukacs博士和James R.Baker，Jr.Eitzman博士是密歇根大学的内科教授，在新陈代谢、炎症和动脉粥样硬化方面拥有丰富的经验。卢卡奇博士是密歇根大学病理学教授兼研究部助理院长，是先天免疫和巨噬细胞生物学领域的领军人物。贝克博士是密歇根生物医学纳米技术研究所的主任，是免疫学和纳米技术方面的世界专家。动脉粥样硬化是冠状动脉疾病最常见的原因，是冠状动脉内皮细胞功能障碍和脂蛋白沉积导致的持续性炎症的结果。据认为，动脉粥样硬化的进展 至少部分原因是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。虽然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在动脉粥样硬化形成不同阶段中的作用尚未明确。我的初步研究表明，甲氨蝶呤(MTX)可以诱导巨噬细胞RVCT，我可以将MTX附着在纳米颗粒支架上，我们可以在体外和体内将MTX输送到巨噬细胞。该建议的目的是确定MTX调节巨噬细胞RevCT的分子机制，并使用巨噬细胞特异性MTX纳米粒在体内抑制动脉粥样硬化形成。我假设甲氨蝶呤能诱导巨噬细胞RVCT，钝化巨噬细胞的炎症反应，减缓动脉粥样硬化的形成。这项建议利用巨噬细胞特异性纳米颗粒的力量，结合分子和基因技术来定义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，这一提议将为将这些新型纳米颗粒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，同时也为候选者在纳米技术、免疫学和血管生物学方面提供坚实的基础。

 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.