Biogenesis and Catabolism of Atherogenic Lipoproteins

致动脉粥样硬化脂蛋白的生物发生和分解代谢

• 批准号: 10628985
• 负责人: M Mahmood Hussain
• 金额: $ 248.53万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10628985
• 关键词: Adipocytes; Adipose tissue; Affect; Anabolism; Animals; Apolipoproteins B; Applications Grants; Arteries; Atherosclerosis; Biogenesis; Bioinformatics; Biological Assay; Biology; Biometry; Blood; Blood Vessels; Cardiovascular Diseases; Catabolism; Cause of Death; Cells; Cholesterol; Chylomicrons; Circulation; Collaborations; Communication; Country; DNA Sequence Alteration; Data; Development; Dietary Fats; Disease; Dissection; Endothelial Cells; Ensure; Evaluation; Event; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Goals; Hepatic; Hepatocyte; Human; Human Genetics; Hypertriglyceridemia; Infiltration; Inflammation; Intervention; Intestines; Intracellular Transport; Knockout Mice; Knowledge acquisition; Link; Lipids; Lipolysis; Lipoprotein (a); Lipoproteins; Liver; Low-Density Lipoproteins; Metabolism; Morality; Morbidity - disease rate; Mus; N-terminal; Outcome; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Process; Production; Program Research Project Grants; Proteins; Proteomics; Research Personnel; Residual state; Resistance; Resources; Risk; Risk Factors; Risk Reduction; Rodent Model; Role; Route; Sampling; Tissues; Translating; Triglyceride Metabolism; Triglycerides; Underrepresented Minority; United States National Institutes of Health; Vascular Endothelial Cell; Very low density lipoprotein; Weight; Work; atherogenesis; atherosclerosis risk; cardiovascular disorder risk; cardiovascular risk factor; clinical application; data management; dietary; experimental study; human data; human tissue; innovation; insight; lipid metabolism; lipidomics; modifiable risk; mouse model; new therapeutic target; non-alcoholic fatty liver disease; novel; novel strategies; personalized medicine; prevent; programs; receptor; synergism; therapeutic target; tool; transcriptomics; transcytosis; uptake

SUMMARY/ABSTRACT – OVERALL: More people die of cardiovascular disease (CVD) than any other disease worldwide. Our proposal focuses on the biogenesis and catabolism of atherogenic apoB- containing lipoproteins (apoB-Lps), which are major risk factors for CVD. ApoB-Lps comprise both cholesterol and triglycerides (TGs). Whereas reducing cholesterol is well established to reduce atherosclerosis, it remains to be convincingly determined whether decreasing levels of TGs or the apoB-Lps that carry TGs will decrease CVD. Blocking secretion of apoB-Lps by the liver reduces levels of cholesterol-rich apoB-Lps, such as LDL and its TG-rich precursor VLDL. Unfortunately, such approaches have led to hepatosteatosis. However, human genetic mutation and animal studies demonstrate that reduced liver secretion of TGs does not invariably cause steatosis. By characterizing novel factors and pathways regulating liver apoB-Lp production, intravascular lipolysis, and adipose TG retention and mobilization, we will identify unique targets to reduce circulating apoB- Lps, their infiltration into the artery wall, and atherosclerosis. We will define basic mechanisms in cells and in new rodent models and then correlate our discoveries with human data, emphasizing a translational and transfomative approach. Our overall goals are to: 1) identify new processes and factors regulating circulating TG and FA levels, 2) investigate the lipidation and intracellular transport of apoB in hepatocytes, and 3) study how different apoB-Lps interact with cells and ultimately catalyze atherogenesis. This application comprises three projects (P1–P3) that have integrated work from three established investigators of apoB-Lp metabolism and atherosclerosis. P1 will investigate the role of adipose MTP and FIT2 in regulating adipose lipolysis, circulating lipids, hepatic apoB-Lp production, and atherosclerosis. P2 will study two poorly characterized proteins in the liver, KLHL12 and FIT2, which control hepatic apoB-Lp lipid-loading and secretion, and the composition of atherogenic apoB-Lps. P3 will study how TG-rich apoB-Lps interact with the vascular wall, and specifically determine the role of the N-terminal region of apoB on lipid uptake and transcytosis of apoB-Lps by vascular ECs and their links to atherosclerosis. The PPG has an administrative core and three scientific cores (C1–C3). The Administrative Core will oversee the overall PPG function and finances. To assist P1–P3, C1 will provide biostatistics and bioinformatics support, C2 will perform lipidomics and proteomics on apoB-Lps and tissues and provide human samples, and C3 will perform state-of-the-art atherosclerosis assays. Our studies will generate novel mouse models invaluable to understand the factors that regulate lipid metabolism and atherosclerosis, identify new therapeutic targets, and better define how high circulating levels of atherogenic apoB-Lps and other factors contribute to atherogenesis. Dissecting pathways that regulate the production and atherogenicity of apoB- Lps promises to reveal novel approaches to reduce CVD. This requires the integration of reseach in our three projects, as experiments in each require assistance from the others and core resources.

摘要/摘要 – 总体而言：死于心血管疾病 (CVD) 的人数比任何国家都多 世界范围内的其他疾病。我们的提案重点关注致动脉粥样硬化 apoB-的生物发生和分解代谢 含有脂蛋白（apoB-Lps），这是CVD的主要危险因素。 ApoB-Lps 包含两种胆固醇 和甘油三酯（TG）。虽然降低胆固醇可以减少动脉粥样硬化，但它仍然存在 有待令人信服地确定 TG 水平下降或携带 TG 的 apoB-Lps 水平是否会下降 化学气相沉积。阻断肝脏分泌 apoB-Lps 可降低富含胆固醇的 apoB-Lps 的水平，例如 LDL 和 其富含 TG 的前体 VLDL。不幸的是，这种方法导致了肝脂肪变性。然而，人类 基因突变和动物研究表明，肝脏 TG 分泌减少并不一定会导致 脂肪变性。通过表征调节肝脏 apoB-Lp 产生的新因子和途径，血管内 脂肪分解、脂肪 TG 保留和动员，我们将确定减少循环 apoB- 的独特目标 Lps，它们渗透到动脉壁，以及动脉粥样硬化。我们将定义细胞和体内的基本机制 新的啮齿动物模型，然后将我们的发现与人类数据相关联，强调转化和 变革性方法。我们的总体目标是：1) 确定调节循环 TG 的新流程和因素 和 FA 水平，2) 研究肝细胞中 apoB 的脂化和细胞内转运，以及 3) 研究如何 不同的 apoB-Lps 与细胞相互作用并最终催化动脉粥样硬化形成。该应用程序包括三个 项目（P1-P3）整合了三位 apoB-Lp 代谢研究人员的工作和 动脉粥样硬化。 P1将研究脂肪MTP和FIT2在调节脂肪分解、循环中的作用 脂质、肝脏 apoB-Lp 产生和动脉粥样硬化。 P2 将研究两个特征不明的蛋白质 肝脏，KLHL12 和 FIT2，控制肝脏 apoB-Lp 脂质负荷和分泌，以及 致动脉粥样硬化apoB-Lps。 P3 将研究富含 TG 的 apoB-Lps 如何与血管壁相互作用，特别是 确定 apoB N 末端区域对血管脂质摄取和 apoB-Lps 转胞吞作用的作用 EC 及其与动脉粥样硬化的联系。 PPG 拥有一个行政核心和三个科学核心 (C1–C3)。 行政核心将监督 PPG 的整体职能和财务。为了协助 P1-P3，C1 将提供 在生物统计学和生物信息学支持下，C2将对apoB-Lps和组织进行脂质组学和蛋白质组学研究 提供人体样本，C3 将进行最先进的动脉粥样硬化检测。我们的研究将产生 新型小鼠模型对于了解调节脂质代谢和动脉粥样硬化的因素非常有价值， 确定新的治疗靶点，并更好地确定致动脉粥样硬化的 apoB-Lps 和其他物质的循环水平有多高 因素导致动脉粥样硬化。剖析调节 apoB- 的产生和致动脉粥样硬化性的途径 Lps 有望揭示减少 CVD 的新方法。这需要我们三个领域的研究整合 作为每个项目的实验，都需要其他项目和核心资源的帮助。