Lipoprotein Interactions in the Vessel Wall

项目总结 我们迫切需要阻止动脉粥样硬化的发生和发展，而不是试图治疗其进展。 处于高级状态。人们普遍认为低密度脂蛋白(LDL)的进入和保留是关键 动脉粥样硬化形成的步骤。然而，我们的数据显示高密度脂蛋白(Hdl)可以与ldl竞争结合。 SR-BI和高密度脂蛋白可与低密度脂蛋白相互作用，减少与蛋白多糖的结合。随着最近意识到 脂蛋白，既有低密度脂蛋白，也有高密度脂蛋白，存在一系列相关但成分不同的亚类，新的 关于脂蛋白亚种形成如何影响动脉粥样硬化的这些点燃步骤的问题已经出现。 这项工作建立在PiShah的K奖(K23HL118132)下产生的数据基础上，表明1)高密度脂蛋白和低密度脂蛋白 以多个亚种的形式存在，2)特定的高密度脂蛋白亚种，其数量、组成(脂质、蛋白质)和 2型糖尿病患者血浆中的功能发生改变，以及3)大的高密度脂蛋白亚类的数量 血浆浓度与心血管风险的早期标志物呈负相关。这项提议还建立在我们的 初步数据显示，高密度脂蛋白调节低密度脂蛋白的细胞转运和与蛋白多糖的结合，但这是 在2型糖尿病的背景下中断。我们的主要假设是低密度脂蛋白和高密度脂蛋白亚种 2型糖尿病患者细胞转运和蛋白多糖结合的不同影响及其平衡的破坏 导致这一人群心血管疾病的高风险。使用互补的方法， 包括对青少年和成年人进行基于动物模型和患者样本的体外细胞分析，我们的目标是 确定和表征与内皮细胞转运有关的低密度脂蛋白和高密度脂蛋白亚型(目标1)和 细胞外蛋白多糖结合(AIM 2)和了解2型糖尿病对这些脂蛋白的影响 亚种(目标3)。这些结果有可能为未来使用重组人的治疗策略提供参考。 防止动脉粥样硬化启动的颗粒或模拟多肽。阻断动脉粥样硬化启动的能力 进展将使年轻人和成年人都受益，特别是患有2型糖尿病的人 增加患心血管疾病的风险。

PROJECT SUMMARY There is a critical need to stop atherosclerosis initiation and progression, rather than trying to treat its progression in an advanced state. It is widely recognized that entry and retention of low density lipoproteins (LDL) are key steps in atherogenesis. However, our data show high density lipoproteins (HDL) can compete with LDL to bind SR-BI and HDL can interact with LDL to decrease binding to proteoglycans. With the recent realization that lipoproteins, both LDL and HDL, exist a series of related but compositionally distinct subpopulations, new questions have arisen as to how lipoprotein subspeciation may affect these igniting steps of atherosclerosis. This work builds on data generated under PI Shah’s K award (K23HL118132) showing that 1) HDL and LDL exist as multiple subspecies, 2) specific HDL subspecies, their amount, composition (lipids, proteins) and function are altered in the plasma of individuals with type 2 diabetes, and 3) the amount of large HDL subspecies in plasma are inversely correlated with early markers of cardiovascular risk. This proposal also builds on our preliminary data that shows HDL modulates both LDL transcytosis and binding to proteoglycans, but this is disrupted in the context of type 2 diabetes. Our overarching hypothesis that that LDL and HDL subspecies differentially impact transcytosis and proteoglycan binding and disruption of their balance in type 2 diabetes contributes to the high risk of cardiovascular disease in this population. Using complementary approaches that include in-vitro cell based assays with animal models and patient samples in adolescents and adults, we aim to identify and characterize the LDL and HDL subspecies involved in endothelial cell transcytosis (Aim 1) and extracellular proteoglycan binding (Aim 2) and to understand the impact of type 2 diabetes on these lipoprotein subspecies (Aim 3). These results have the potential to inform future therapeutic strategies to use recombinant particles or mimetic peptides to prevent atherosclerosis initiation. The ability to block atherosclerosis initiation and progression will benefit both youth and adults, and particularly individuals with type 2 diabetes who are at increased risk for cardiovascular disease.