DIET, AROMATIC AMINO ACIDS, AND CNS NEUROTRANSMITTERS

饮食、芳香氨基酸和中枢神经系统神经递质

• 批准号: 2199302
• 负责人: JOHN D FERNSTROM
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2199302
• 关键词: PC12 cells; adrenal medulla; binding proteins; blood chemistry; brain metabolism; catecholamines; diet; dietary aminoacid; dietary carbohydrates; dietary lipid; dietary proteins; dopamine; enzyme substrate; exercise; fasting; high performance liquid chromatography; insulin; laboratory rat; neurotransmitter biosynthesis; nutrient bioavailability; nutrition related tag; phenylalanine; radiotracer; serotonin; serum albumin; tissue /cell culture; tryptophan; tryptophan 5 monooxygenase; tyrosine; tyrosine 3 monooxygenase

This competing renewal application will examine biochemical/metabolic mechanisms underlying the effects of food on the synthesis of two brain neurotransmitters, serotonin (5HT) and dopamine (DA). 5HT and DA synthesis rates reflect brain levels of their respective substrates, tryptophan (TRP) and tyrosine (TYR), because the rate-limiting enzymes TRP and TYR hydroxylase are unsaturated with substrate. Brain TRP and TYR levels, in turn, are influenced by their uptake from blood, mediated by a competitive transport system shared by all large neutral amino acids [LNAA], including TRP and TYR. Brain TRP uptake may also be influenced by TRP binding to serum albumin. Our proposed studies for TRP->5HT will examine mechanisms by which food ingestion modifies brain TRP uptake (and 5HT synthesis), studying in particular the importance of the meal's protein content, acting via changes in serum LNAA levels, and its fat content, acting via changes in albumin binding of TRP (post-meal changes in serum non-esterified fatty acid [NEFA] levels alter TRP binding to albumin). We will also examine the effects of exercise, and its interaction with meals on serum TRP binding, brain TRP levels and 5HT synthesis: Exercise elevates serum NEFA levels, reduces TRP binding, and may thus raise brain TRP and 5HT. For TYR->DA, we will examine PHE as a substrate for DA synthesis, and the relative roles of PHE and TYR in overall DA [catecholamine (CAM)] synthesis, in vitro and in vivo. We will also study whether PHE and TYR uptake into brain and adrenal medulla, a model for peripheral CAN neurons, are similar, and whether food ingestion produces similar effects on PHE and TYR levels, (and CAM synthesis) at each site. For studies in vivo, we will employ rats; for studies in vitro, we will employ PC12 cells and bovine adrenal medullary cells. TRP, TYR and PHE levels, and 5HT and DA synthesis will be measured by HPLC in brain and adrenal medulla following acute or chronic food ingestion, or amino acid injection, or in cell cultures incubated with TYR, PHE or both together. Results should provide a more definitive understanding of one mechanism by which diet appears to inform the brain regarding what has recently been consumed, alone and possibly within the context of other metabolic events (here, those stimulated by exercise). Our data will also add important new information on the relative roles of TYR and PHE as substrates in CAM synthesis, and the impact of diet on CAM synthesis, acting via changes it produces in the neuronal pools of each substrate.

这种竞争性的更新应用程序将检查生化/代谢 食物对两种大脑合成的影响机制 神经递质5-羟色胺（5-HT）和多巴胺（DA）。5 ht和DA 合成速率反映了它们各自底物的脑水平， 色氨酸（TRP）和酪氨酸（TYR），因为限速酶 TRP和TYR羟化酶与底物是不饱和的。 脑TRP和 TYR水平反过来又受其从血液中摄取的影响， 通过所有大分子中性氨基酸共享的竞争性运输系统 [LNAA]，包括TRP和TYR。 脑TRP摄取也可能受到 通过TRP与血清白蛋白结合。 我们提出的TRP-> 5 HT研究将 研究食物摄入改变大脑TRP摄取的机制（以及 5羟色胺合成），特别是研究膳食的重要性， 蛋白质含量，通过血清LNAA水平的变化起作用， 含量，通过TRP的白蛋白结合变化（餐后变化）起作用 血清中非酯化脂肪酸[NEFA]水平改变TRP与 白蛋白）。 我们还将研究运动的影响， 与膳食的相互作用对血清TRP结合、脑TRP水平和5 HT的影响 综合：运动提高血清NEFA水平，减少TRP结合， 可使脑TRP和5 HT升高。 对于TYR->DA，我们将检查PHE作为 DA合成的底物，以及PHE和TYR在 体外和体内总DA [儿茶酚胺（CAM）]合成。 我们 还将研究PHE和TYR摄取是否进入大脑和肾上腺 骨髓（外周CAN神经元的模型）是相似的，以及是否 食物摄入对PHE和TYR水平（以及CAM）产生类似的影响 合成）。 对于体内研究，我们将使用大鼠; 在体外研究中，我们将采用PC 12细胞和牛肾上腺髓质细胞， 细胞 TRP，TYR和PHE水平，以及5 HT和DA合成将被 急性或慢性给药后，通过HPLC测定脑和肾上腺髓质中的 食物摄入或氨基酸注射，或在细胞培养物中孵育 与TYR、PHE或两者一起。 结果应该提供一个更明确的 了解饮食似乎是如何告知大脑的一种机制， 关于最近消费的东西，单独和可能在 其他代谢事件的背景（在这里，那些由运动刺激的）。 我们的数据还将增加关于以下方面的相对作用的重要新信息： 酪氨酸和苯丙氨酸作为CAM合成的底物，以及饮食对CAM的影响 合成，通过它在每个神经元池中产生的变化起作用。 衬底