B12 ABSORPTION, KINETICS AND TRANSCOBALAMIN GENOTYPE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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行性疾病，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缺乏的主要原因是由于恶性贫血和萎缩性胃炎引起的吸收不良。在初步研究中，间接证据表明B12转运蛋白transcobalamin II中的常见多态性（776 CG）影响B12吸收和向组织的递送。因此，这种多态性可能会影响一个人？由于吸收不良而导致的B12缺乏症。 本研究的目的是评估B12在人体中的吸收和动力学，并确定776 CG多态性对这些参数的影响。为了实现这一目标，将采用与劳伦斯利弗莫尔国家实验室合作的一项重大技术进步，称为加速器质谱法（AMS）。AMS提供了检测生物样品中阿摩尔浓度的碳-14（14 C）水平的能力。因此，该技术特别适合于检测口服摄入即使是小的、放射性最低的底物后血液、尿液和粪便中14 C的出现。本提案的具体目的是利用AMS评估14 C标记的B12在健康人受试者中的吸收和动力学，这些受试者具有不同的转钴胺素II多态性变体。这些研究的结果将提供有关B12生物处理的重要基本信息，并可能最终深入了解B12缺乏对退行性疾病风险的贡献。此外，预计AMS技术将提供开发一种敏感和特异性方法的手段，用于评估疑似B12吸收不良的人的B12吸收能力。 到目前为止，该项目的工作已经导致了今年发表的以下论文，并在2006年4月的研究亮点部分。 放大图片作者：Stephen R.放大图片作者：Jozsef Lango，布鲁斯A.作者：布赫霍尔茨，约书亚W.放大图片作者：米勒，拉尔夫绿色，布鲁斯D. Hammock，John R.罗斯和彼得J.安德森。人体维生素B12的吸收和代谢通过加速器质谱法使用特定标记的14 C-钴胺素来测量。PNAS 103（2006）5694-5699。 已经合成了一批新的维生素B12，预计明年将完成新的剂量实验。

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.