Blood TG clearance and vascular biology

血液 TG 清除率和血管生物学

基本信息

批准号：
10628992
负责人：
Ira J Goldberg
金额：
$ 63.42万
依托单位：
NYU LONG ISLAND SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10628992
关键词：
Acceleration Activins Adipocytes Affect Apolipoproteins B Arteries Atherosclerosis Binding Biogenesis Biology Blood Blood Vessels Cardiovascular Diseases Catabolism Cells Cellular Metabolic Process Cellular biology Characteristics Cholesterol Chronic Chylomicrons Data Development Endothelial Cells Endothelium Enterocytes Event Fasting Fatty acid glycerol esters Gene Expression Genes Goals Hepatic Hepatocyte Human In Vitro Inflammation Inflammatory Intestines Knock-out Knockout Mice Ligand Binding Link Lipids Lipolysis Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Lysosomes Macrophage Mediating Movement Mus N-terminal Pathway interactions Peptides Phosphotransferases Postprandial Period Prevention Process Production Protein Deficiency Proteomics RNA Reporting Research Personnel Role SR-BI receptor Site Source Testing Tissues Triglycerides Vascular Diseases Very low density lipoprotein bafilomycin A endothelial cell scavenger receptor extracellular vesicles feeding impression in vivo lipidomics lipoprotein lipase microsomal triglyceride transfer protein novel novel strategies receptor single cell analysis transcytosis uptake vascular inflammation western diet

项目摘要

ABSTRACT The first steps in atherosclerosis are the transendothelial movement and subendothelial accumulation of lipoprotein lipid. Endothelial cell (EC) transcytosis of LDL involves two receptors, scavenger receptor-BI (SR-BI) and activin-like kinase 1 (ALK1). We showed that ECs also internalize undigested chylomicrons via SR-BI and process them in lysosomes, leading to storage of some lipid as lipid droplets and the release of small extracellular vesicles (sEVs) that cause lipid accumulation in macrophages. While many have considered chylomicrons as non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that lipoprotein entry into the artery is a receptor-mediated process. The overall goal of Project 3 (P3) is to determine how EC chylomicron uptake affects EC biology, delivers lipids to the artery, and accelerates atherosclerosis. In Aim 1, we propose to determine how triglyceride-rich lipoproteins (TRLs) from the liver and intestines are internalized and either processed within ECs or transcytosed. To do this, we will use mice with selective knockout of liver and intestinal microsomal triglyceride transfer protein (MTP) obtained from Dr. Hussain (P1) to determine lipoprotein characteristics that determine their interaction with SR-BI and ALK1. We will also determine how lipoproteins created with liver FIT2 knockout (P2) affect EC inflammation and the production and composition of EC released sEVs. Our preliminary data show that the N-terminal region of apoB has separate ligand binding regions for ALK1 and SR-BI and this aim will determine why and how lipoprotein uptake via each of these receptors affects ECs. In Aim 2, we propose in vivo studies to determine whether postprandial lipemia leads to EC inflammation and whether the site of origin of these TRLs determines their effects on arterial ECs. We provide preliminary data suggesting that chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use N-terminal fragments of apoB to reduce lipoprotein uptake into ECs to determine role(s) of ALK1 and SR-BI in EC inflammation and atherosclerosis. Completion of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, determine whether TRLs from liver and intestine have similar effects on ECs, and define a novel approach to atherosclerosis prevention.

抽象的动脉粥样硬化的第一步是跨内皮运动和内皮下积累脂蛋白脂质。 LDL 的内皮细胞 (EC) 转胞吞作用涉及两种受体：清道夫受体-BI (SR-BI) 和激活素样激酶 1 (ALK1)。我们发现 EC 还通过 SR-BI 内化未消化的乳糜微粒在溶酶体中处理它们，导致一些脂质以脂滴的形式储存并释放出小的细胞外导致巨噬细胞脂质积累的囊泡（sEV）。虽然许多人认为乳糜微粒是非动脉粥样硬化且太大而无法穿过 EC 屏障，这个概念现在已经过时了，因为人们认识到脂蛋白进入动脉是一个受体介导的过程。项目 3 (P3) 的总体目标是确定 EC 乳糜微粒摄取如何影响 EC 生物学、向动脉输送脂质并加速动脉粥样硬化。在目标 1，我们建议确定肝脏和肠道中富含甘油三酯的脂蛋白 (TRL) 的含量内化并在 EC 内加工或转胞吞。为此，我们将使用选择性基因敲除小鼠肝脏和肠道微粒体甘油三酯转移蛋白 (MTP) 从 Hussain 博士 (P1) 获得，以确定脂蛋白特性决定了它们与 SR-BI 和 ALK1 的相互作用。我们还将确定如何肝脏 FIT2 敲除 (P2) 产生的脂蛋白影响 EC 炎症以及 EC 发布了 sEV。我们的初步数据表明apoB的N端区域具有单独的配体结合 ALK1 和 SR-BI 区域，这一目标将决定脂蛋白通过这些区域摄取的原因和方式受体影响 EC。在目标 2 中，我们提出体内研究以确定餐后脂血症是否会导致 EC 炎症以及这些 TRL 的起源部位是否决定了它们对动脉 EC 的影响。我们提供初步数据表明，脂蛋白脂肪酶 (LpL) 缺陷小鼠中积累的乳糜微粒增加动脉粥样硬化。我们将使用 apoB 的 N 端片段来减少 EC 中的脂蛋白摄取，以确定 ALK1 和 SR-BI 在 EC 炎症和动脉粥样硬化中的作用。完成拟议的研究承诺为了改变我们对乳糜微粒与血管疾病关系的看法，确定 TRL 是否来自肝脏和肠道对内皮细胞也有类似的影响，并定义了一种预防动脉粥样硬化的新方法。