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

在大脑中，脂肪酸调节许多功能，包括血液流动、信号转导和炎症，最终可以影响行为。然而，大脑维持其脂肪酸浓度的机制尚未达成一致。我的nserc资助的实验室已经积累了证据，证明血浆中未酯化的多不饱和脂肪酸通过非选择性机制进入大脑，然后在大脑中选择性地进行酯化或分解代谢。我们现在有新的和改进的方法来回答多不饱和脂肪酸是如何进入大脑并在体内处理的。这项拨款申请的目的是确定脂肪酸在体内进入大脑并被大脑代谢的机制。在这个模型中，未酯化脂肪酸被注入一只清醒、自由生活的大鼠的静脉中，实验以高能、头部聚焦的微波固定（nserc资助的设备）结束。因此，我们的第一组实验将是测试，在口服给药的情况下，血浆池对脑脂肪酸摄取的贡献。我们还将测试是否可以通过增加未标记的DHA和EPA的浓度来减少放射性标记的DHA和EPA在体内进入大脑的摄入量。我们也期望EPA能被迅速而广泛地氧化。此外，在本应用中，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 -氧化是否是其在脑磷脂中浓度如此之低的原因。在进行体内脑摄取方法之前，通过将候选脂肪酸转运蛋白抑制剂注入大脑，我们将能够测试候选脂肪酸转运蛋白的抑制是否会减少体内脑脂肪酸摄取。在大脑中，脂肪酸与信号转导相耦合并且具有选择性靶点（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，而且还可能导致新的或改进的成像方法。在我们的项目中，HQP将获得营养科学，数学建模以及与神经化学领域相关的几种方法的经验，包括动物模型，色谱和质谱。

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.