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

• 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
• 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

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.

项目总结 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。 新出现的数据表明，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(HDL)介导，具体归因于天然脂蛋白数量和功能的减少 高密度脂蛋白。因此，合成的高密度脂蛋白纳米粒(HDLNPs)已被提出为下一代治疗药物 治疗这些疾病。然而，由于材料的发展已经远远落后于 生物学的发现和理解，导致了临床上代价高昂的失败，强化了绝望的 需要高密度脂蛋白启发疗法的新方法。要想成功，合成的高密度脂蛋白NPs必须准确 在大小、形状、胆固醇吸收能力和操作所需的功能能力上模仿本地高密度脂蛋白 并以有效的方式运输细胞胆固醇。为此，我们正在寻求发展，为第一 时间，一种综合的策略，调整高密度脂蛋白NP，使其形式和功能可以精致和优化 围绕本机HDL定义的一组参数进行操作。为此，我们构建了一种生物- 通过组装高密度脂蛋白定义的载脂蛋白A-I(apo A-I)和磷脂来激发高密度脂蛋白NP模拟 围绕多功能有机核心(MOC)模板。这种方法似乎非常有希望，因为这些 有机高密度脂蛋白纳米粒(OHDLNPs)在大小(~10 nm)和外排能力上与天然高密度脂蛋白非常相似 来自富含脂质的巨噬细胞的胆固醇。在此，我们提出了优化OHDL族化合物的合成和纯化方法 NPS，通过MOC和下游合成步骤的调制，表征OHDLNP，量化 高密度脂蛋白纳米粒排出和内流胆固醇的能力以及在体外减少炎症和减少 动脉粥样硬化小鼠模型中的动脉粥样硬化斑块负荷。通过这些研究，我们将产生一个 高密度脂蛋白纳米粒调节胆固醇流量的最佳疗法，并在体外和体内证明 高密度脂蛋白纳米粒在减少炎症和动脉粥样硬化斑块形成方面的有效性。