Regulation of Low-Affinity Folate Transporters in the Brain

大脑中低亲和力叶酸转运蛋白的调节

• 批准号: RGPIN-2015-04459
• 负责人: Bendayan, Reina
• 金额: $ 2.4万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612977
• 关键词: Regulation; Low; Affinity; Folate; Transporters

Folates are water soluble vitamins that play a critical role in tissue development, function and repair. Humans must obtain folate from their diet since they cannot synthesize it from other nutrients. Folate deficiency is one of the major dietary health problems worldwide and is associated with significant disturbances that affect tissues such as bone marrow, intestine and developing brain. Folates being negatively charged water soluble molecules at physiological pH cross biological membranes very poorly by diffusion and thus need specific membrane carriers (transporters) for intestinal uptake and to gain access to vital organs such as the brain. A number of folate transporters have been identified in several tissues including the intestine, kidney and brain. In particular, the folate receptors alpha (FRa) constitutes a major transport pathway in the brain. Folate transport is critical for the maintenance of normal brain function. FRa mutations and/or presence of antibodies against this receptor can cause severe folate deficiency and result in childhood neurodegeneration. To date, folate transport in the brain has been largely investigated through the FRa; however, little is known on the properties of other folate transporters in the brain. Apart from the FRa, there are at least two other transport systems for folates, which have lower affinity for folates compared to FRa, i.e. require higher folate concentrations. In the intestine, folate transport is mediated by the proton-coupled folate transporter (PCFT) which functions optimally at acidic pH. The reduced folate carrier (RFC) is another low affinity folate transporter which exchanges folate with other inorganic or organic anions. At present, the contribution of these transporters to the overall brain folate uptake remains unclear. Recent studies report that PCFT and RFC can be regulated by nuclear receptors, in particular, the vitamin D receptor (VDR). We propose that in the context of FRa mutations and/or presence of FRa antibodies which render this mechanism of folate transport ineffective, the low affinity folate transporters could play a significant role in brain folate uptake. Furthermore, the induction of the same transporters may provide alternative routes for effective folate penetration into the brain. The objectives of this proposal are to investigate the contribution of the low affinity folate transporters, PCTF and RFC, in folate uptake by several brain cellular models and to examine the role of nuclear receptors i.e., VDR, in folate transporter regulation using animal mouse models lacking FRa. It is anticipated that an induction of the folate transporters i.e., PCFT, through administration of specific VDR ligands will result in an enhanced brain uptake of folate derivatives. This work could uncover novel strategies for the treatment of brain disorders caused by folic acid deficiency.

叶酸是水溶性维生素，在组织发育、功能和修复中起着关键作用。人类必须从他们的饮食中获得叶酸，因为他们不能从其他营养素中合成它。叶酸缺乏是世界范围内的主要饮食健康问题之一，并与影响骨髓，肠道和发育中的大脑等组织的严重干扰有关。叶酸是在生理pH下带负电荷的水溶性分子，其通过扩散穿过生物膜的能力非常差，因此需要特定的膜载体（转运蛋白）用于肠摄取并进入重要器官如脑。已经在包括肠、肾和脑在内的几种组织中鉴定出许多叶酸转运蛋白。特别地，叶酸受体α（FRa）构成脑中的主要转运途径。叶酸转运对于维持正常的大脑功能至关重要。FRa突变和/或针对该受体的抗体的存在可引起严重的叶酸缺乏症并导致儿童神经退行性变。迄今为止，叶酸在大脑中的转运主要是通过FRa进行研究的;然而，对大脑中其他叶酸转运蛋白的性质知之甚少。除了FRa之外，还有至少两种其他的叶酸转运系统，与FRa相比，它们对叶酸的亲和力较低，即需要较高的叶酸浓度。在肠道中，叶酸转运由质子偶联叶酸转运蛋白（PCFT）介导，其在酸性pH下发挥最佳作用。还原叶酸载体（RFC）是另一种低亲和力叶酸转运蛋白，其与其他无机或有机阴离子交换叶酸。目前，这些转运蛋白对整个脑叶酸摄取的贡献仍不清楚。最近的研究报告，PCFT和RFC可以由核受体，特别是维生素D受体（VDR）调节。我们提出，在FRa突变和/或FRa抗体的存在下，使这种叶酸转运机制无效，低亲和力叶酸转运蛋白可能在脑叶酸摄取中发挥重要作用。此外，相同转运蛋白的诱导可能为叶酸有效渗透到脑中提供替代途径。本提案的目的是研究低亲和力叶酸转运蛋白PCTF和RFC在几种脑细胞模型的叶酸摄取中的作用，并检查核受体的作用，即，VDR，使用缺乏FRa的动物小鼠模型进行叶酸转运蛋白调节。预期叶酸转运蛋白的诱导，PCFT通过给予特定的VDR配体将导致叶酸衍生物的脑摄取增强。这项工作可能会发现治疗叶酸缺乏引起的大脑疾病的新策略。