Vascular Biochemistry of Vitamin B12

维生素 B12 的血管生物化学

• 批准号: 6882690
• 负责人: Donald Weldon Jacobsen
• 金额: $ 34.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882690
• 关键词: SDS polyacrylamide gel electrophoresis; binding proteins; biochemistry; biological signal transduction; cardiovascular disorder risk; clinical research; cobalamin; cobamide; enzyme activity; glutathione; high performance liquid chromatography; homocysteine; homocystinuria; human tissue; nutrition related tag; polymerase chain reaction; radiotracer; tissue /cell culture; transcytosis; vascular endothelium; vascular smooth muscle; vitamin B12; vitamin B12 coenzyme; vitamin metabolism; vitamin receptor

DESCRIPTION (provided by applicant): The micronutrient B12 (cobalamin, Cbl) plays an essential role in homocysteine metabolism in most if not all cells in the body. Hyperhomocysteinemia is a major independent risk factor for cardiovascular disease and is also associated with other devastating conditions such as neural tube defects and Alzheimer's disease. The determinants of hyperhomocysteinemia are multifactorial and include both genetic and acquired conditions. Cobalamin transport, processing and coenzyme formation by cardiovascular cells and tissues is a neglected area of research. The long-term objectives of this proposal are to gain an understanding of 1) Cbl transport processes in cultured human aortic endothelial cells and smooth muscle cells, 2) Cbl processing within these cells, and 3) the conversion of Cbl vitamers to methylcobalamin and adenosylcobalamin, coenzymes for cytosolic methionine synthase and mitochondrial methylmalonyI-CoA mutase, respectively. This study is driven by the hypotheses that 1) the vascular endotheliurn plays an essential role in maintaining Cbl homeostasis throughout the body; 2) it does so by a//owing the Cbl-binding protein transcobalarnin to transcytose from the/urinal/(apical/) space to the ablurninal (basolateral) space with Cbl as its cargo; 3) endothelial ceil injury, as occurs in atherogenesis and atherosclerosis, may cause localized disruption of Cbl homeostasis; and 4) Cbl deficiency itself/f is a cause of vascular ceil dysfunction due to a breakdown of the hornocysteine rernethylation machinery, which leads to hyperhornocysteinernia. The Specific Aims of this proposal are: 1) to establish the mechanisms of Cbl transport and transcytosis in cultured human aortic endothelial and smooth muscle cells; 2) to determine how Cbl is processed in cultured vascular cells and the role that glutathionyl-Cbl plays in this processing; and 3) to elucidate the mechanisms of Cbl coenzyme formation in cultured human aortic endothelial and smooth muscle cells.

描述（由申请人提供）：微量营养素 B12（钴胺素，Cbl）在体内大多数（如果不是全部）细胞的同型半胱氨酸代谢中发挥重要作用。高同型半胱氨酸血症是心血管疾病的一个主要独立危险因素，也与其他破坏性病症有关，例如神经管缺陷和阿尔茨海默氏病。高同型半胱氨酸血症的决定因素是多因素的，包括遗传和后天条件。心血管细胞和组织的钴胺素转运、加工和辅酶形成是一个被忽视的研究领域。该提案的长期目标是了解 1) 培养的人主动脉内皮细胞和平滑肌细胞中的 Cbl 转运过程，2) 这些细胞内的 Cbl 加工，以及 3) Cbl 维生素体转化为甲基钴胺素和腺苷钴胺素、胞质蛋氨酸合酶和线粒体甲基丙二酰辅酶 A 变位酶的辅酶， 分别。这项研究的假设是：1) 血管内皮细胞在维持全身 Cbl 稳态方面发挥着重要作用； 2) 它通过//使 Cbl 结合蛋白转钴平衡蛋白以 Cbl 作为其货物从/小便/(顶端/)空间转胞吞至远侧(基底外侧)空间； 3) 动脉粥样硬化和动脉粥样硬化中发生的内皮细胞损伤可能会导致 Cbl 稳态的局部破坏； 4) Cbl 缺乏本身/f 是由于角质半胱氨酸再甲基化机制崩溃而导致血管细胞功能障碍的原因，从而导致高角质半胱氨酸血症。该提案的具体目标是：1）建立培养的人主动脉内皮细胞和平滑肌细胞中Cbl转运和转胞吞作用的机制； 2) 确定Cbl在培养的血管细胞中的加工方式以及谷胱甘肽-Cbl在此加工中所起的作用； 3) 阐明培养的人主动脉内皮细胞和平滑肌细胞中 Cbl 辅酶形成的机制。