Lipoprotein Interactions in the Vessel Wall

项目摘要 目前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 在一个先进的国家。低密度脂蛋白（LDL）的进入和保留是 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HDL可以与LDL相互作用以减少与蛋白聚糖的结合。随着最近意识到， 脂蛋白，LDL和HDL，存在一系列相关但组成不同的亚群，新的 已经出现了关于脂蛋白亚种类如何影响动脉粥样硬化的这些引发步骤的问题。 这项工作建立在PI Shah的K奖（K23 HL 118132）产生的数据基础上，显示1）HDL和LDL 作为多个亚种存在，2）特定HDL亚种，其量、组成（脂质、蛋白质）和 2型糖尿病患者血浆中的高密度脂蛋白（HDL）功能改变，以及3）大HDL亚种的量 与心血管风险的早期标志物呈负相关。这一建议还建立在我们的 初步数据显示，HDL调节LDL转胞吞作用和与蛋白聚糖的结合，但这是 在2型糖尿病的背景下被破坏。我们的总体假设是低密度脂蛋白和高密度脂蛋白亚种 2型糖尿病中对转胞吞作用和蛋白聚糖结合的不同影响及其平衡的破坏 导致了这一人群患心血管疾病的高风险。使用补充方法， 包括在青少年和成人中使用动物模型和患者样本进行的基于体外细胞的测定，我们的目标是 鉴定和表征参与内皮细胞转胞吞作用的LDL和HDL亚种（目的1）， 细胞外蛋白聚糖结合（Aim 2），并了解2型糖尿病对这些脂蛋白的影响 亚种（Aim 3）。这些结果有可能为未来的治疗策略提供信息， 颗粒或模拟肽来预防动脉粥样硬化起始。阻断动脉粥样硬化起始的能力 和进展将有利于青年和成年人，特别是2型糖尿病患者谁是在 增加心血管疾病的风险。

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.