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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：该提案描述了一项为期5年的培训计划，以开发心血管医学，纳米技术和免疫学方面的独立物理科学家。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期奖学金。候选人将获得密歇根大学心血管医学主任戴维·宾斯基（David J. Drs将提供会议制度。 Daniel Eitzman，Nick Lukacs和James R. Baker，Jr。Eitzman博士是密歇根大学的内科教授，在代谢，创新和动脉粥样硬化方面拥有丰富的经验。 Lukacs博士是密歇根大学的病理学教授和研究学院助理院长，他是先天免疫学和巨噬细胞生物学的领导者。密歇根州纳米技术研究所主任贝克博士是免疫学和纳米技术的世界专家。动脉粥样硬化是冠状动脉疾病的最常见原因，是由冠状动脉脂蛋白沉积驱动的内皮功能障碍和持续感染的结果。人们认为动脉粥样硬化的进展尽管很明显，脂蛋白和巨噬细胞与动脉粥样硬化有关，但尚未定义两者与巨噬细胞RevCT在不同阶段的巨噬细胞之间的关系。我的初步研究表明，Methogotyoxate（MTX）诱导了巨噬细胞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传递到巨噬细胞。该提案的目的是定义MTX调节巨噬细胞REVCT的分子机制，并使用巨噬细胞特异性的MTX纳米颗粒在体内抑制动脉粥样硬化。我假设MTX诱导了巨噬细胞Revct，巨噬细胞炎症反应中的钝化并减慢了动脉粥样硬化。该建议利用巨噬细胞特异性纳米颗粒与分子和遗传技术结合的功能来定义MTX的抗动脉粥样硬化特性以及巨噬细胞REVCT如何贡献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的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，同时还为候选人提供了纳米技术，免疫学和血管生物学的强大基础。