Mechanisms involved in maintaining brain fatty acid concentrations: Uptake and metabolism.

在大脑中，脂肪酸调节许多功能，包括血流、信号转导和炎症，最终影响行为。 然而，大脑维持脂肪酸浓度的机制尚未达成一致。我的 NSERC 资助的实验室积累的证据表明，来自血浆未酯化池的多不饱和脂肪酸通过非选择性机制进入大脑，然后在大脑内选择性地进行酯化或分解代谢。 我们现在有了新的和改进的方法来回答多不饱和脂肪酸如何进入大脑并在体内进行处理。 该拨款申请的目的是确定脂肪酸进入大脑并在体内代谢的机制。 在该模型中，将未酯化的脂肪酸注入清醒、自由生活的大鼠的静脉中，并通过高能头部聚焦微波固定（NSERC 资助的设备）终止实验。因此，我们的第一组实验将是测试口服给药后血浆池对脑脂肪酸摄取的贡献。 我们还将测试体内放射性标记的 DHA 和 EPA 是否可以通过增加未标记的 DHA 和 EPA 的浓度来减少大脑的摄取。 我们还预计 EPA 会被快速、广泛地氧化。 此外，在本申请中，我们建议用肉碱棕榈酰转移酶-1 的化学抑制剂来阻断 EPA 的 β 氧化。 这将告诉我们 EPA β-氧化是否是其在脑磷脂中浓度如此低的原因。 通过在进行体内脑摄取方法之前将候选脂肪酸转运蛋白的抑制剂注入大脑，我们将能够测试候选脂肪酸转运蛋白的抑制是否会降低体内脑脂肪酸的摄取。 在大脑中，脂肪酸与信号转导耦合并具有选择性靶标（磷脂酰肌醇），这项工作不仅将提高我们对大脑生物学的基本理解，而且可能会带来新的或改进的成像方法。 我们项目中的 HQP 将获得营养科学、数学建模以及与神经化学领域相关的多种方法（包括动物模型、色谱法和 MS）方面的经验。

In the brain, fatty acids regulate many functions including blood flow, signal transduction and inflammation which, ultimately, can influence behavior. However, the mechanisms by which the brain maintains it fatty acid concentrations are not agreed upon. My NSERC-funded laboratory has accumulated evidence that polyunsaturated fatty acids, from the plasma unesterified pool, enter the brain via a non-selective mechanism and then are selectively partitioned to esterification or catabolism within the brain. We now have new and improved methods to answer how polyunsaturated fatty acids enter the brain and are handled in vivo. The objective of this grant application is to identify the mechanisms by which fatty acids enter and are metabolized by the brain in vivo. In this model unesterified fatty acids are infused into the vein of an awake, free-living rat and the experiment is terminated with high-energy, head-focused microwave fixation (NSERC-funded equipment). Thus, our first set of experiments will be to test, upon oral administration, what plasma pools contribute to brain fatty acid uptake. We will also test if radiolabelled DHA and EPA uptake into the brain, in vivo, can be reduced by increasing the concentration of non-labeled DHA and EPA. We also expect EPA to be rapidly and extensively beta-oxidized. Furthermore, in this application, we propose to block the beta-oxidation of EPA with a chemical inhibitor of carnitine palmitoyl transferase-1. This will tell us if EPA beta-oxidation is the reason its concentration is so low within brain phospholipids. By infusing inhibitors of candidate fatty acid transporters into the brain prior to performing our in vivo brain uptake method, we will be able to test if inhibition of candidate fatty acid transporters decreases brain fatty acid uptake in vivo. In the brain, fatty acids are coupled to signal transduction and have selective targets (phosphatidyl inositol) not only will this work improve our basic understanding of brain biology, but it could lead to new or improved imaging methods. HQP in our program will get experience in Nutritional Sciences, mathematical modeling and several methods associated with the field of neurochemistry including animal models, chromatography and MS.