Spatial Delivery of MicroRNA Inhibitor via Targeted Polyelectrolyte Complex Micelles to Treat Atherosclerosis.

通过靶向聚电解质复合胶束空间递送 MicroRNA 抑制剂来治疗动脉粥样硬化。

基本信息

批准号：
10229491
负责人：
Yun Fang
金额：
$ 39.48万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229491
关键词：
ATP-Binding Cassette Transporters Address Affect American Arterial Fatty Streak Arteries Atherosclerosis Attention Attenuated Binding Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cholesterol Cholesterol Homeostasis Communities Complex Data Disease Encapsulated Endothelial Cells Endothelium Engineering Event Excretory function Fibrin Foam Cells Future Goals Health Hematological Disease High Density Lipoproteins In Vitro Inflammation Investigation Ischemia LDL Cholesterol Lipoproteins Lesion Lipoproteins Liver Malignant Neoplasms Medical Micelles MicroRNAs Molecular Morbidity - disease rate Myocardial Infarction Nature Peptides Permeability Pharmacological Treatment Process Regulator Genes Risk Factors Site Stroke System Testing Therapeutic Tissues Vascular Cell Adhesion Molecule-1 athero susceptible base beta-Chemokines chemokine receptor effectiveness evaluation gamma-Chemokines hypercholesterolemia in vivo inhibitor/antagonist innovation macrophage monocyte mortality nanomaterials nanomedicine nanoparticle nanoparticle delivery novel novel strategies novel therapeutic intervention particle preclinical development prevent recruit research clinical testing reverse cholesterol transport vascular inflammation

项目摘要

Project Summary Atherosclerotic vascular disease and downstream tissue ischemia (heart attacks, strokes) remain the leading cause of morbidity and mortality among Americans. Atherosclerosis (thickening and hardening of vas- cular walls) develops preferentially at arterial sites of curvature and bifurcation where disturbed blood flow is prevalent; yet, current pharmacological treatments of atherosclerosis principally target “systemic” risk factors such as high blood cholesterol. We believe targeted nanomedicine has unique potential to revolutionize future medical practice of atherosclerosis by correcting disease-causing molecular mechanisms “regionally” in dis- eased blood vessels. Arterial wall-based therapy is attractive given the focal nature of atherosclerosis at predictable vascular sites. Disturbed flow increases endothelial permeability and promotes endothelial inflammation, leading to the subendothelial retention of low-density lipoprotein (LDL) cholesterol particles and monocytes accumulation. Lesion monocytes mature into macrophages and internalize lipoproteins. Excess cellular cholesterol effluxed from macrophages is transported by high density lipoproteins (HDL) to the liver for excretion through a process known as Reverse Cholesterol Transport (RCT). Inadequate RCT is associated with cholesterol-loaded mac- rophage “foam cells”. Extensive studies suggest that inhibition of endothelial inflammation and promotion of macrophage cholesterol efflux are ideal strategies to prevent or regress atherosclerosis. Nevertheless, it re- mains extremely difficult to modulate these disease-causing molecular mechanisms “spatially” in lesions. microRNAs (miRNAs) are critical gene regulators of cellular events related to atherosclerosis. Disturbed flow increases endothelial miR-92a to promote vascular inflammation while elevated miR-33a suppresses cho- lesterol efflux. The overall goal of this project is to develop a new nanomedicine-based therapeutic strategy against atherosclerosis, aiming to inhibit endothelial miR-92a and suppress macrophage miR-33a in a lesion- specific fashion. Our key premise is that this new strategy, if successful, could mitigate the tremendous health burden of atherosclerosis. Indeed, our preliminary data suggest that this can be done. We have employed tar- geting peptides against fibrin and Vascular Cell Adhesion Molecule 1 (VCAM-1) to drive active binding of nano- materials to atherosclerotic lesions and inflamed endothelia, respectively. Moreover, peptides against C-C chemokine receptor type 2 (CCR2) successfully delivered nanoparticles to lesion monocytes/macrophages. To address our overall goal, we hold two immediate objectives. First, we will refine and test a novel polyelectrolyte complex micelle system to deliver miR-92a inhibitor specifically to athero-susceptible endotheli- um. Second, this polyelectrolyte complex micelle will be reformulated to display peptides against lesion macro- phages to deliver inhibitors against miR-33a. These studies should further preclinical development, and per- haps eventual clinical testing, of a new therapeutic strategy to treat atherosclerosis, a still critically important disease process.

项目摘要动脉粥样硬化血管疾病和下游组织缺血（心脏病发作，中风）仍然是美国人发病和死亡的主要原因。动脉粥样硬化（增厚和硬化克莱尔壁）在曲率和分叉的动脉部位优先发展，在影响血流的情况下流行;然而，动脉粥样硬化的当前药物治疗主要针对“全身”风险因素例如高血胆固醇。我们认为，靶向纳米医学具有独特的潜力来革新未来动脉粥样硬化的医学实践是通过“区域性”纠正引起疾病的分子机制的医学实践容易的血管。鉴于动脉粥样硬化在可预测的血管上的焦点，基于动脉壁的治疗具有吸引力站点。流动干扰会增加内皮渗透性并促进内皮感染，导致低密度脂蛋白（LDL）胆固醇颗粒和单核细胞积累的下皮下皮保留。病变单核细胞成熟成巨噬细胞并内化脂蛋白。过量的细胞胆固醇排出通过高密度脂蛋白（HDL）从巨噬细胞中运输到肝脏以通过一项突出称为反向胆固醇运输（RCT）。 RCT不足与负载的MAC- r裂“泡沫细胞”。广泛的研究表明，抑制内皮感染和促进巨噬细胞胆固醇外排是预防或消退动脉粥样硬化的理想策略。然而，它重新电源在病变中“空间上”调节这些引起疾病的分子机制极为困难。 microRNA（miRNA）是与动脉粥样硬化有关的细胞事件的关键基因调节剂。不安流动增加内皮miR-92a以促进血管炎症，而升高的miR-33a抑制了CHO- Lesterol外排。该项目的总体目标是制定新的基于纳米医学的理论策略针对动脉粥样硬化，旨在抑制内皮miR-92a并抑制病变中的巨噬细胞miR-33a 特定的时尚。我们的主要前提是，如果成功的话，这种新策略可以减轻巨大的健康动脉粥样硬化的负担。确实，我们的初步数据表明可以做到这一点。我们已经工作了焦油 - 使肽对纤维蛋白和血管细胞粘附分子1（VCAM-1）驱动纳米的主动结合分别为动脉粥样硬化病变和发炎的内皮材料。而且，针对C-C的肽趋化因子受体2型（CCR2）成功地将纳米颗粒传递到病变单核细胞/巨噬细胞。为了解决我们的整体目标，我们持有两个直接的目标。首先，我们将完善并测试一本小说聚电解质复合胶束系统，以将miR-92a抑制剂专门传递到可动脉粥样硬化的内皮上嗯。其次，该聚电解质复合物胶束将被重新制定，以显示针对病变宏观的肽噬菌体以提供针对miR-33a的抑制剂。这些研究应进一步发展，并 HAPS最终的临床测试是一种治疗动脉粥样硬化的新治疗策略，这仍然非常重要疾病过程。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Polymorphism in peptide self-assembly visualized.

DOI：
10.1073/pnas.2123197119
发表时间：
2022-02-08
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Tirrell M
通讯作者：
Tirrell M

Harnessing the Therapeutic Potential of Biomacromolecules through Intracellular Delivery of Nucleic Acids, Peptides, and Proteins.