Highly Functional Organic Core Templated High-Density Lipoproteins to Reverse Vascular Disease

高功能有机核心模板化高密度脂蛋白可逆转血管疾病

基本信息

批准号：
9900703
负责人：
SonBinh TheBao Nguyen
金额：
$ 19.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900703
关键词：
Activities of Daily Living Acute Address Age Amides Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Apolipoprotein A-I Area Arterial Fatty Streak Arteries Atherosclerosis Back Binding Biological Caliber Cardiac Cause of Death Cells Cerebrovascular Disorders Chemistry Cholesterol Cholesterol Esters Chronic Clinic Complex Critical Pathways DNA Data Dementia Deposition Development Diabetes Mellitus Disease Excision Failure Generations Goals Gold Half-Life Hepatocyte High Density Lipoprotein therapy High Density Lipoproteins In Vitro Inflammation Intervention LDL Cholesterol Lipoproteins Lead Lecithin Length Link Lipid-Laden Macrophage Lipids Low-Density Lipoproteins Malignant Neoplasms Measures Mediating Medical Myelogenous Oligonucleotides Pathway interactions Patients Pharmaceutical Preparations Phospholipids Process Property Proteins Recombinants Renal clearance function Residual state Safety Saline Shapes Solid Structure Surface Therapeutic Time Transferase Translations Treatment Efficacy Trees Vascular Diseases aging population analog biomaterial compatibility burden of illness cardiovascular disorder risk cost experimental study flexibility in vivo macrophage mimetics mouse model nanoGold nanoparticle next generation novel strategies novel therapeutics particle receptor scaffold sound stem success therapeutic nanoparticles uptake

项目摘要

PROJECT SUMMARY Cholesterol has been linked to several cardiac and brain vascular diseases, dementias, diabetes, and cancer. Emerging data suggests that such diseases can be traced back to an imbalance in cholesterol transport mediated by high-density lipoproteins (HDLs), specifically attributed to reduced amount and function of native HDLs. As such, synthetic HDL nanoparticles (HDL NPs) have been proposed as next-generation therapeutics for treating these diseases. However, because the development of materials has lagged far behind the pace of biological discovery and understanding, costly failures in the clinic have resulted, reinforcing the desperate need for new approaches to HDL-inspired therapies. To be successful, synthetic HDL NPs must accurately mimic native HDLs in size, shape, cholesterol-uptake capacity, and functional capacity required to manipulate and transport cellular cholesterol in an effective manner. To this end, we are seeking to develop, for the first time, a synthetic strategy to tune HDL NPs so that their form and function can be exquisitely and optimally manipulated around a set of parameters defined by native HDLs. To that end, we have constructed a bio- inspired HDL NP mimetic by assembling the HDL-defining apolipoprotein A-I (apo A-I) and phospholipids around multifunctional organic core (MOC) templates. This approach appears to be highly promising, as these organic HDL NPs (OHDL NPs) closely mimic natural HDLs in their size (~10 nm) and ability to efflux cholesterol from lipid-laden macrophages. Here we propose to optimize the synthesis and purification of OHDL NPs, through modulation of the MOC and downstream synthetic steps, characterize the OHDL NPs, quantify the ability of OHDL NPs to efflux and influx cholesterol and reduce inflammation in vitro, and reduce atherosclerotic plaque burden in a mouse model of atherosclerosis. Through these studies we will generate an optimal OHDL NP therapeutic for the modulation of cholesterol flux, and demonstrate both in vitro and in vivo the efficacy of OHDL NPs at reducing inflammation and atherosclerotic plaque formation.

项目摘要胆固醇与多种心脏和脑血管疾病，痴呆症，糖尿病和癌症有关。新兴数据表明，这些疾病可以追溯到胆固醇运输的不平衡由高密度脂蛋白（HDLS）介导的，特别归因于天然的量和功能降低和功能 HDLS。因此，已提出合成HDL纳米颗粒（HDL NP）为下一代治疗药治疗这些疾病。但是，因为材料的开发远远落后于生物学发现和理解，诊所中的昂贵失败已经导致，加强了绝望的需要新方法以进行HDL启发的疗法。为了成功，合成的HDL NP必须准确模仿大小，形状，胆固醇摄取能力和操纵所需的功能能力的天然HDL 并以有效的方式运输细胞胆固醇。为此，我们正在寻求发展，第一个时间，是调整HDL NP的合成策略围绕由本机HDL定义的一组参数操作。为此，我们构建了一个生物通过组装定义HDL定义的载脂蛋白A-I（APO A-I）和磷脂来启发HDL NP模拟物周围多功能有机芯（MOC）模板。这种方法似乎是非常有前途的有机HDL NP（OHDL NP）与它们的大小（〜10 nm）紧密模仿自然HDL和排出能力来自脂质巨噬细胞的胆固醇。在这里，我们建议优化OHDL的合成和纯化 NP通过调节MOC和下游合成步骤，表征OHDL NP，量化 OHDL NP的外流和涌入胆固醇的能力并减少体外炎症，并减少动脉粥样硬化模型中的动脉粥样硬化斑块负担。通过这些研究，我们将产生用于调节胆固醇通量的最佳OHDL NP治疗性，并在体外和体内展示 OHDL NP在减少炎症和动脉粥样硬化斑块形成方面的功效。