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

项目摘要 胆固醇与几种心脑血管疾病、痴呆、糖尿病和癌症有关。 新出现的数据表明，这类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，特别是由于天然脂蛋白的数量和功能减少， HDL。因此，已提出合成HDL纳米颗粒（HDL NPs）作为下一代治疗剂 来治疗这些疾病。然而，由于材料的发展远远落后于 生物学的发现和理解，在临床上代价高昂的失败，加强了绝望的 需要HDL启发疗法的新方法。为了成功，合成HDL NPs必须准确地 在大小、形状、胆固醇摄取能力和操纵所需的功能能力方面模仿天然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，首先是 时间，一种调整HDL NPs的合成策略，使它们的形式和功能可以精致和优化。 围绕由本地HDL定义的一组参数进行操作。为此，我们建立了一个生物- 通过组装HDL-定义载脂蛋白A-I（apo A-I）和磷脂 多功能有机核心（MOC）模板。这种方法似乎很有前途，因为这些 有机HDL NPs（OHDL NPs）在其大小（~10 nm）和流出能力方面与天然HDL非常相似 胆固醇从充满脂质的巨噬细胞。在此，我们建议优化OHDL的合成和纯化 通过MOC和下游合成步骤的调节，NP表征OHDL NP， OHDL NPs流出和流入胆固醇和减少体外炎症的能力，以及减少 在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 最佳的OHDL NP治疗调节胆固醇流量，并证明在体外和体内 OHDL NP在减少炎症和动脉粥样硬化斑块形成方面的功效。

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.