Role of Dietary Nutrients in Induction of Pseudocapillarization and the Functional Consequences for Hyperlipidemia

膳食营养素在诱导假性毛细血管化中的作用以及高脂血症的功能性后果

• 批准号: 10674261
• 负责人: LAURIE D DELEVE
• 金额: $ 33.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674261
• 关键词: Advanced Glycosylation End Products; Aging; Animals; Antisense Oligonucleotides; Atherosclerosis; Blood Circulation; Bone Marrow; Cardiovascular Diseases; Chronic; Clinical; Confocal Microscopy; Diet; Dietary intake; Endocytosis; Endothelial Cells; Enzymes; Exposure to; Fibrinogen; Food; Glycolates; Goals; Human; Hyperlipidemia; Impairment; In Vitro; Incidence; Intake; Kupffer Cells; Lactoylglutathione Lyase; Lead; Life; Link; Lipids; Literature; Liver; Methodology; Modernization; Molecular; Morphology; Nitric Oxide; Nitric Oxide Pathway; Nutrient; Pathway interactions; Phenotype; Platelet-Derived Growth Factor; Process; Production; Rattus; Residual state; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Therapeutic; Therapeutic Effect; Thrombospondin 1; Tissues; Visit; aged; arginase; atherosclerosis risk; cardiovascular disorder risk; cell age; chylomicron remnant; dietary; endothelial stem cell; food preparation; improved; in vivo; knock-down; macromolecule; oxidized LDL receptors; oxidized low density lipoprotein; receptor mediated endocytosis; restoration; scavenger receptor

ABSTRACT The central tenet of this proposal is that the modern diet is enhanced in dietary nutrients due to food preparation techniques and a shift in dietary nutrients that leads over many years leads to a process called pseudocapillarization. Pseudocapillarization is defined as an ultrastructural change of liver sinusoidal endothelial cells (LSECs) that is seen in aging experimental animals and also in humans starting as early as the 4th decade of life. Pseudocapillarized LSECs also demonstrate functional changes, specifically in their ability to endocytose certain substrates. Pseudocapillarization has been linked to changes in serum lipids that are partially responsive or unresponsive to statin therapy and therefore contribute to the so-called residual risk for atherosclerosis (i.e. not treatable with statins). The overall objectives of this application are to understand the mechanisms that link dietary enhancements to morphological and functional changes seen in LSECs in aging, to establish the impact of these changes on hyperlipidemia, and to determine whether therapeutic strategies to reverse the aged LSEC phenotype might be clinically beneficial. Specific aims: aim 1 will examine possible pathways that link dietary changes to signaling that downregulates the nitric oxide pathway in LSECs to determine the aberrant signaling that leads to pseudocapillarization. Aim 2 will use cutting-edge methodology to re-examine the mechanism of chylomicron remnant clearance; will examine approaches to either reverse pseudocapillarization in aged rats or exacerbate the change in LSECs and examine the effect on post-prandial lipid profiles, lipid clearance by LSECs, LSEC endocytosis and ultrastructure; and will examine the endocytotic machinery involved in lipid clearance in LSECs from young rats, old rats and old rats with reversal of pseudocapillarization.

抽象的 该提议的核心宗旨是，由于食物而饮食中的现代饮食增强了 制备技术和饮食营养素的转变多年来导致过程 称为假毛细血管。假毛细血管化定义为肝脏的超微结构变化 正弦内皮细胞（LSEC），在老化的实验动物以及人类中也可见 早在生命的第四个十年开始。伪毛细血管的LSEC也表现出功能变化， 特别是它们具有内吞底物的能力。假毛细血管已与 对他汀类药物疗法的部分反应或无反应的血清脂质的变化，因此 有助于动脉粥样硬化的所谓残留风险（即用他汀类药物治疗）。 该应用程序的总体目标是了解将饮食联系起来的机制 LSEC在衰老中看到的形态和功能变化的增强，以建立影响 在高脂血症上的这些变化，并确定是否会扭转老年人的治疗策略 LSEC表型在临床上可能是有益的。 具体目的：AIM 1将检查将饮食变化与信号联系起来的可能途径 下调LSEC中的一氧化氮途径，以确定导致的异常信号传导 假毛细血管化。 AIM 2将使用尖端方法来重新检查 乳糜微粒残留清除；将研究老年人的伪毛细血管化的方法 大鼠或加剧LSEC的变化，并检查对餐后脂质曲线的影响 LSEC，LSEC内吞作用和超微结构的清除；并将检查内吞机械 参与来自年轻老鼠，老鼠和老鼠的LSEC的脂质清除，逆转 假毛细血管化。