Lipoprotein Interactions in the Vessel Wall

血管壁中脂蛋白的相互作用

• 批准号: 10589111
• 负责人: W Sean Davidson
• 金额: $ 54.89万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589111
• 关键词: Adolescent; Adult; Affect; Age; Animal Model; Animals; Arteries; Atherosclerosis; Binding; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Data; Endothelial Cells; Endothelium; Equilibrium; Event; Exhibits; Family; Functional disorder; Future; High Density Lipoproteins; Human; In Vitro; Individual; K-Series Research Career Programs; LDL Cholesterol Lipoproteins; Lipids; Lipoprotein Binding; Lipoproteins; Longevity; Low-Density Lipoproteins; Mediating; Mus; Non-Insulin-Dependent Diabetes Mellitus; Patients; Persons; Plasma; Population; Process; Proteins; Proteoglycan; Proteomics; Recombinants; Regulation; Role; SR-BI receptor; Sampling; Series; Specimen; Surface Plasmon Resonance; Testing; Therapeutic; Vascular Endothelium; Work; Youth; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; cohort; extracellular; feasibility testing; high density lipoprotein receptor; high risk; insight; lipidomics; particle; peptidomimetics; premature; prevent; transcytosis

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.

项目摘要 迫切需要阻止动脉粥样硬化的倡议和进展，而不是试图治疗其进展 处于高级状态。广泛认识到低密度脂蛋白（LDL）的进入和保留是关键 动脉粥样硬化的步骤。但是，我们的数据显示高密度脂蛋白（HDL）可以与LDL竞争以结合 SR-BI和HDL可以与LDL相互作用，以降低与蛋白聚糖的结合。随着最近意识到 LDL和HDL都存在脂蛋白，都存在一系列相关但综合不同的亚群，新的 关于脂蛋白的实质如何影响动脉粥样硬化的这些点火步骤，已经出现了问题。 这项工作建立在Pi Shah奖（K23HL118132）下生成的数据的基础上，显示1）HDL和LDL 以多种亚种的形式存在，2）特定的HDL亚种，其数量，成分（脂质，蛋白质）和 2型糖尿病个体的血浆中的功能发生了变化，3）大HDL亚种的量 在血浆中，与心血管风险的早期标记成反比。该建议也基于我们 初步数据显示HDL调节了LDL跨胞菌病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LDL和HDL亚种 在2型糖尿病中的差异影响转胞胞细胞增多和蛋白聚糖的结合和平衡的破坏 在该人群中导致心血管疾病的高风险。使用完整的方法 在青少年和成年人中包括使用动物模型和患者样本的基于体外细胞的测定，我们的目标是 识别并表征与内皮细胞转胞胞菌病有关的LDL和HDL亚种（AIM 1）和 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（目标3）。这些结果有可能告知未来使用重组的治疗策略 颗粒或模拟辣椒，以防止动脉粥样硬化倡议。阻止动脉粥样硬化倡议的能力 进步将使青年和成年人，尤其是患有2型糖尿病的人受益 心血管疾病的风险增加。