Regulation of Low-Affinity Folate Transporters in the Brain

叶酸是一种水溶性维生素，在组织发育、功能和修复中发挥着关键作用。人类必须从饮食中获得叶酸，因为他们不能从其他营养物质中合成叶酸。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紊乱有关。叶酸在生理pH下是带负电荷的水溶性分子，很难通过扩散穿过生物膜，因此需要特定的膜载体(转运体)来进行肠道摄取，并进入大脑等重要器官。已在包括肠、肾和脑在内的几个组织中发现了许多叶酸转运体。特别是，叶酸受体α(FRA)构成了大脑中一条主要的运输途径。叶酸转运对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导致严重的叶酸缺乏，并导致儿童神经变性。到目前为止，叶酸在大脑中的运输在很大程度上是通过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。除联邦铁路局外，至少还有另外两种叶酸运输系统，与联邦铁路局相比，它们对叶酸的亲和力较低，即需要更高的叶酸浓度。在肠道中，叶酸的转运是由质子偶联的叶酸转运蛋白(PCFT)介导的，该转运蛋白在酸性pH条件下发挥最佳功能。还原叶酸载体(RFC)是另一种与其他无机或有机阴离子交换叶酸的低亲和力叶酸转运体。目前，这些转运蛋白对大脑整体叶酸摄取的贡献尚不清楚。最近的研究报道，PCFT和RFC可以受核受体，特别是维生素D受体(VDR)的调节。我们认为，在FRA突变和/或存在使叶酸转运机制失效的FRA抗体的背景下，低亲和力的叶酸转运体可能在大脑叶酸摄取中发挥重要作用。此外，相同转运体的诱导可能为叶酸有效地渗透到大脑提供了替代途径。本研究的目的是研究低亲和力叶酸转运体PCTF和RFC在几种脑细胞模型叶酸摄取中的作用，并利用缺乏FRA的动物模型研究核受体VDR在叶酸转运体调节中的作用。预计通过给予特定的VDR配体来诱导叶酸转运体，即PCFT，将导致大脑对叶酸衍生物的摄取增加。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。

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.