Brain Signaling of Essential Amino Acid Deficiency

描述（由申请人提供）：充足的氨基酸（AA）营养对人类和动物的健康和福祉至关重要。由于AA没有储存库，因此可能会迅速发生不可或缺的AA（IAA）缺乏症，特别是如果已经存在轻度蛋白质缺乏症。IAA缺乏已被证明会损害依赖于蛋白质合成的生长和身体功能，如伤口愈合。然而，生长减少归因于IAA不平衡实际上是继发于食物摄入量减少，一种对IAA缺乏的厌食反应。由于AA补充剂已成为时尚，特别是“健康食品”时尚人士，节食者和运动员可能会使用，因此应将IAA失衡视为潜在的健康危害。此外，患有癌症恶病质、AA代谢紊乱和其他代谢紊乱的个体也可能患有IAA比例失调，这可能会损害他们的恢复。该实验室的长期目标是确定大脑如何识别IAA缺乏。鉴于AA营养的重要性，我们必须更好地了解IAA失衡影响大脑功能的基本机制。我们正在研究这些机制与一个良好的描述营养模型，使用大鼠喂养AA-不平衡的饮食（IMB）。我们最近的工作表明，在行为（进食率）的变化，以响应IMB发生在第一个12分钟的喂养。在这段时间内，我们发现APC中谷氨酰胺和谷氨酸盐增加。体外快速变化包括信号转导途径的激活和AA转运蛋白的动员。基于我们对该模型的了解，我们提出了以下具体目标：1）鉴定APC中IAA缺乏的初始代谢信号; 2）鉴定由具体目标1中鉴定的代谢信号激活的信号转导途径;以及3）鉴定APC的信号IAA缺乏的代谢能输出细胞中的激活机制。我们假设如下：相对过量的AA增加AA代谢，刺激谷氨酰胺-谷氨酸循环，导致信号通路的激活和APC神经元的增强。当APC神经元被激活时，它们的AA能输出首先作用于AMPA受体，向大脑的其他部分发出AA缺乏的信号，以产生厌食反应。

DESCRIPTION (provided by applicant): Adequate amino acid (AA) nutrition is essential for the health and well being of humans and animals alike. Because AAs have no storage pool, the development of an indispensable AA (IAA) deficiency can occur rapidly, particularly if a mild state of protein deficiency already exists. IAA deficiencies have been shown to compromise growth and body function that depends on protein synthesis, such as wound healing. However, the growth reduction attributed to IAA imbalance is actually secondary to decreased food intake, an anorectic response to the IAA deficiency. Since AA supplements have become fashionable, and may be used particularly by "health food" faddists, dieters and athletes, IAA imbalance should be recognized as a potential health hazard. Moreover, individuals with cancer cachexia, disorders of AA metabolism, and other metabolic disorders may also suffer IAA disproportion, which could compromise their recovery. The long-term goal of the work in this laboratory is to determine how the brain recognizes IAA deficiency. Given the importance of AA nutrition, it is imperative that we gain a better understanding of the basic mechanisms by which IAA imbalance affects brain function. We are investigating these mechanisms with a well-described nutritional model using rats fed AA-imbalanced diets (IMB). Our recent work indicates that changes in behavior (rate of eating) in response to IMB occur within the first 12 min of feeding. Within this time period we have found increased glutamine and glutamate in the APC. Rapid changes in vitro include an activation of signal transduction pathways and mobilization of AA transporters. Based on our knowledge of this model, we propose the following specific aims: 1) to identify the initial metabolic signal(s) of IAA deficiency in the APC; 2) to identify the signal transduction pathways activated by the metabolic signals identified in Specific Aim 1; and 3) to identify the mechanisms of activation in the glutamatergic output cells of the APC that signal IAA deficiency. We hypothesize the following: The relative excess of AAs other than the limiting one increase AA metabolism and stimulate the glutamineglutamate cycle, leading to the activation of signaling pathways and the potentiation of APC neurons. When APC neurons are activated, their glutamatergic output first acts at AMPA receptors to signal AA deficiency to other parts of the brain for the anorectic responses.