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; 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 - 总体上：与任何人死于心血管疾病（CVD）的人要多 全球其他疾病。我们的建议着重于动脉粥样硬化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包括两个胆固醇 和甘油三酸酯（TGS）。降低胆固醇以减少动脉粥样硬化，但仍保持 令人信服地确定降低TGS或携带TGS的APOB-LPS是否会减少 CVD。肝脏对APOB-LP的分泌降低了富含胆固醇的APOB-LP的水平，例如LDL和 它的TG富含前体VLDL。不幸的是，这种方法导致了肝脏病。但是，人类 遗传突变和动物研究表明，TGS的肝脏分泌减少并不总是引起 脂肪变性。通过表征控制肝APOB-LP产生的新因素和途径，血管内 脂解和脂肪TG保留和动员，我们将确定独特的目标，以减少循环的APOB- LPS，它们渗入动脉壁和动脉粥样硬化。我们将定义细胞和中的基本机制 新的啮齿动物模型，然后将我们的发现与人类数据相关联，强调翻译和 转疗方法。我们的总体目标是：1）确定调节循环TG的新过程和因素 2）研究肝细胞中APOB的脂质和细胞内转运，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。此应用程序包括三个 已经整合了来自APOB-LP代谢和 动脉粥样硬化。 P1将研究脂肪MTP和FIT2在调节脂肪脂解中的作用，循环 脂质，肝素APOB-LP产生和动脉粥样硬化。 P2将研究两种特征较差的蛋白质 肝脏，KLHL12和FIT2，控制肝apob-lp脂质加载和分泌，以及组成 动脉粥样硬化APOB-LPS。 P3将研究富含TG的APOB-LP如何与血管壁相互作用，特别是 确定APOB的N末端区域在血管中对APOB-LP的脂质摄取和转胞膜的作用 EC及其与动脉粥样硬化的联系。 PPG具有行政核心和三个科学核心（C1 – C3）。 管理核心将监督整体PPG功能和财务。为了协助P1 – P3，C1将提供 生物统计学和生物信息学支持，C2将对APOB-LPS和组织以及 提供人类样品，C3将执行最新的动脉粥样硬化测定法。我们的研究将产生 新颖的小鼠模型宝贵了解调节脂质代谢和动脉粥样硬化的因素， 确定新的治疗靶标，并更好地定义循环水平高的动脉粥样硬化APOB-LP和其他 因素有助于动脉粥样硬化。剖析调节Apob-的生产和动脉粥样硬化的途径 LPS有望揭示减少CVD的新方法。这需要在我们的三个 项目，因为每个实验都需要其他人的帮助和核心资源。