B12 ABSORPTION, KINETICS AND TRANSCOBALAMIN GENOTYPE

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 维生素 B12 缺乏症在老年人以及发展中国家的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行性变，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导致的吸收不良。 在初步研究中，已获得间接证据表明 B12 转运蛋白转钴胺素 II 中常见的多态性 (776CG) 会影响 B12 的吸收和向组织的输送。 因此，这种多态性可能会影响个体对吸收不良引起的 B12 缺乏的易感性。 本研究的目标是评估人体维生素 B12 的吸收和动力学，并确定 776CG 多态性对这些参数的影响。 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获得的一项重大技术进步，即加速器质谱法 (AMS)。 AMS 能够检测生物样品中阿摩尔浓度的碳 14 (14C) 水平。 因此，该技术特别适合检测口服摄入少量放射性物质后血液、尿液和粪便中 14C 的出现情况。 该提案的具体目标是利用 AMS 评估健康人类受试者中 14C 标记的 B12 的吸收和动力学，这些受试者的不同之处在于其所拥有的转钴胺素 II 多态性变体。 这些研究的结果将提供有关 B12 生物处理的重要基础信息，并可能最终深入了解 B12 缺乏对退行性疾病风险的影响。 此外，预计 AMS 技术将提供一种手段来开发一种敏感且特异的方法，用于评估怀疑患有 B12 吸收不良的人类的 B12 吸收能力。

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.