B12 ABSORPTION, KINETICS AND TRANSCOBALAMIN GENOTYPE

B12 吸收、动力学和转钴胺基因型

• 批准号: 7359012
• 负责人: JOSHUA WILLIAM MILLER
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359012
• 关键词: B12; ABSORPTION; KINETICS; TRANSCOBALAMIN; GENOTYPE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vitamin B12 deficiency is common in older adults, as well as in children and young adults in developing countries. Potential consequences of B12 deficiency include megaloblastic anemia and neurological degeneration, as well as increased risk of degenerative disorders such as vascular disease, cancer, and loss of cognitive function. The primary cause of B12 deficiency is malabsorption due to pernicious anemia and atrophic gastritis. In preliminary studies, circumstantial evidence has been obtained suggesting that a common polymorphism (776CG) in the B12 transport protein, transcobalamin II, affects B12 absorption and delivery to the tissues. Consequently, this polymorphism may influence an individual?s susceptibility to B12 deficiency caused by malabsorption. The goals of the present study are to assess B12 absorption and kinetics in humans, and to determine the influence of the 776CG polymorphism on these parameters. To accomplish this goal, a major technological advance available through collaboration with the Lawrence Livermore National Laboratories, called Accelerator Mass Spectrometry (AMS), will be employed. AMS provides the capacity to detect levels of carbon-14 (14C) in biological samples at attomolar concentrations. The technology is thus uniquely suited to detect the appearance of 14C in the blood, urine, and feces after oral ingestion of even small, minimally radioactive substrates. The specific aims of this proposal are to exploit AMS to assess the absorption and kinetics of 14C-labelled B12 in healthy human subjects who differ by which polymorphic variant of transcobalamin II they possess. The results of these studies will provide important basic information about the biological handling of B12 and may ultimately provide insight into the contribution of B12 deficiency to the risk of degenerative disease. Moreover, it is anticipated that the AMS technology will provide the means to develop a sensitive and specific method for assessment of B12 absorptive capacity in humans suspected of B12 malabsorption. Work on the project to date has resulted in the publication of the following paper this year and is presented in the Research Highlights section of this 2006 APR. Colleen Carkeet, Stephen R. Dueker, Jozsef Lango, Bruce A. Buchholz, Joshua W. Miller, Ralph Green, Bruce D. Hammock, John R. Roth and Peter J. Anderson. Human vitamin B12 absorption and metabolism are measured by accelerator mass spectrometry using specifically labeled 14C-cobalamin. PNAS 103 (2006) 5694-5699. A new batch of vitamin B12 has been synthesized and it is anticipated that new dosing experiments will be completed in the next year.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。维生素B12缺乏症在发展中国家的老年人以及儿童和年轻人中很常见。B12缺乏的潜在后果包括巨幼细胞性贫血和神经退化，以及血管疾病、癌症和认知功能丧失等退行性疾病的风险增加。B12缺乏的主要原因是恶性贫血和萎缩性胃炎引起的吸收不良。在初步研究中，已有间接证据表明，B12转运蛋白中一个常见的多态(776CG)影响B12的吸收和向组织的输送。因此，该基因多态性可能影响S吸收不良所致的B12缺乏症的易感性。本研究的目的是评估人类对B12的吸收和动力学，并确定776CG多态对这些参数的影响。为了实现这一目标，将采用通过与劳伦斯·利弗莫尔国家实验室合作而获得的一项重大技术进步，称为加速器质谱学(AMS)。AMS提供了在大摩尔浓度下检测生物样品中碳-14(14C)水平的能力。因此，该技术特别适合于检测口服摄入即使是微小的、最低放射性的底物后，血液、尿液和粪便中14C的出现。这项建议的具体目的是利用AMS来评估14C标记的B12在健康受试者中的吸收和动力学，这些受试者因他们拥有哪种多态的转钴胺II变体而不同。这些研究的结果将提供有关B12生物处理的重要基本信息，并最终可能提供关于B12缺乏对退行性疾病风险的贡献的洞察。此外，预计AMS技术将为评估疑似B12吸收不良的人类的B12吸收能力提供一种敏感和具体的方法。到目前为止，关于该项目的工作已导致今年发表了以下论文，并在2006年年度报告的研究要点一节中提出。科琳·卡基特、斯蒂芬·R·杜克、约泽夫·兰戈、布鲁斯·A·布赫霍尔茨、约书亚·W·米勒、拉尔夫·格林、布鲁斯·D·汉莫克、约翰·R·罗斯和彼得·J·安德森。人类维生素B12的吸收和代谢是用加速器质谱仪测量的，使用专门标记的14C-钴胺。PNAS 103(2006)5694-5699。新一批维生素B12已经合成，预计明年将完成新的剂量试验。