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 该提案的中心原则是现代饮食由于食物而增强了膳食营养 多年来的制备技术和膳食营养素的转变导致了一个过程 称为假毛细血管化。假性毛细血管化被定义为肝脏超微结构的改变 窦状内皮细胞 (LSEC)，见于衰老实验动物和人类 早在生命的第四个十年就开始了。假毛细血管化的 LSEC 也表现出功能变化， 特别是它们内吞某些底物的能力。假毛细血管化与 对他汀类药物治疗部分反应或无反应的血脂变化，因此 导致所谓的动脉粥样硬化残留风险（即不能用他汀类药物治疗）。 该应用程序的总体目标是了解将饮食联系起来的机制 衰老过程中 LSEC 形态和功能变化的增强，以确定其影响 这些变化对高脂血症的影响，并确定是否有逆转衰老的治疗策略 LSEC 表型可能在临床上有益。 具体目标：目标 1 将研究将饮食变化与信号传递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 假毛细血管化。目标2将利用前沿的方法论重新审视其机制 乳糜微粒残留清除；将研究逆转老年假毛细血管化的方法 大鼠或加剧 LSEC 的变化并检查对餐后血脂谱、血脂的影响 LSEC 清除、LSEC 内吞作用和超微结构；并将检查内吞机制 参与年轻大鼠、老年大鼠和老年大鼠 LSEC 中的脂质清除，并逆转 假毛细血管化。