Mechanism of omega-6 and omega-3 fatty acid transport across the blood brain barrier

脂肪酸（FAs）对发育和成熟的中枢神经系统都很重要。虽然大脑可以制造一些脂肪酸，但有许多多不饱和脂肪酸（PUFA），包括亚油酸（LA）和α亚麻酸（ALA），必须通过饮食获得。此外，大脑制造关键的必需omega-6和omega-3 PUFA如二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的能力有限。这些必需脂肪酸被吸收到血液中，并通过形成血脑屏障（BBB）的脑微血管内皮细胞进入大脑。此外，促炎性脂肪酸如花生四烯酸（AA）如何进入大脑并改变大脑功能尚不清楚。拟议的研究将研究FA如何通过BBB运输，重点是主要通过饮食和AA（一种已知的促炎FA）获得的PUFA。我们的假设是，必需的PUFAs，ALA，EPA和DHA通过脑微血管内皮细胞中表达的特定脂肪酸转运蛋白进行跨BBB的转运，AA不仅可以显著改变BBB FA转运，还可以改变其他膜转运特性。该提案的目标是：1.确定omega-6和omega-3脂肪酸跨血脑屏障的转运机制，2.检查这些FA在脑微血管中的细胞加工过程。3.评价FA短期（即2-60 min）和长期（即24-48 h）暴露对BBB功能的影响。这些研究将为PUFA在脑内的转运和分布机制以及PUFA对BBB功能的影响提供重要信息。鉴于有关PUFA在人脑功能中至关重要的证据，所提出的研究对于各种PUFA在大脑发育和治疗中枢神经系统相关疾病如阿尔茨海默氏病、抑郁症、精神分裂症、注意力缺陷和多动症中的应用至关重要。

Fatty acids (FAs) are important to both the developing and mature central nervous system. While the brain can make some fatty acids, there are a number of polyunsaturated fatty acids (PUFAs) including linoleic acid (LA) and alpha linolenic acid (ALA) that must be obtained through the diet. In addition, the brain has a limited ability to make key essential omega-6 and omega-3 PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These essential fatty acids are absorbed into the bloodstream and enter the brain through brain microvessel endothelial cells that form the blood-brain barrier (BBB). In addition, how proinflammatory FAs such as arachidonic acid (AA) enter into the brain and alter brain function is unknown. The proposed research will examine how FA transport across the BBB occurs with a focus on the PUFAs which are primarily obtained through the diet and on AA, a known proinflammatory FA. Our hypothesis is that the essential PUFAs, ALA, EPA and DHA undergo transport across the BBB through specific fatty acid transport proteins expressed in the brain microvessel endothelial cells and that AA may dramatically alter not only BBB FA transport but also other membrane transport properties. The objectives of the proposal are to: 1. Determine the mechanisms for transport of omega-6 and omega-3 fatty acids across the BBB., 2. Examine the cellular processing of these FAs in the brain microvasculature., 3. Evaluate the effects of both short-term (i.e. 2-60 min) and long-term (i.e. 24-48 h) exposure of FAs on BBB function. The proposed studies will provide important information concerning the mechanisms involved in PUFA transport and distribution in the brain and the effects of PUFAs on BBB function. Given the evidence concerning the vital importance of PUFA in human brain function, the proposed studies are fundamental to the application of various PUFA in the development of the brain and the treatment of central nervous system related diseases such as Alzheimer's disease , depression, schizophrenia, attention deficit and hyperactivity disorders.