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。由于氨基酸没有储存池，因此不可缺少的氨基酸（IAA）缺乏症可能迅速发生，特别是在已经存在轻度蛋白质缺乏症的情况下。IAA缺乏已被证明会损害生长和依赖蛋白质合成的身体功能，如伤口愈合。然而，IAA失衡导致的生长减少实际上是继发于食物摄入减少，这是对IAA缺乏的厌食反应。由于AA补充剂已经成为一种时尚，特别是“健康食品”时尚者、节食者和运动员可能会使用，因此应该认识到AA失衡是一种潜在的健康危害。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出现IAA失调，从而影响其康复。这个实验室的长期目标是确定大脑是如何识别IAA缺乏的。鉴于AA营养的重要性，我们有必要更好地了解IAA失衡影响大脑功能的基本机制。我们正在用一个描述良好的营养模型来研究这些机制，该模型使用的是喂食aa -不平衡饮食（IMB）的大鼠。我们最近的研究表明，对IMB反应的行为（进食速度）变化发生在喂食的前12分钟内。在这段时间内，我们发现APC中谷氨酰胺和谷氨酸增加。体外的快速变化包括信号转导途径的激活和AA转运体的动员。基于我们对该模型的了解，我们提出了以下具体目标：1)确定APC中IAA缺乏的初始代谢信号；2)识别特异性Aim 1中识别的代谢信号激活的信号转导途径；3)确定谷氨酸能输出细胞的激活机制，该细胞是IAA缺乏的信号。我们的假设如下：除限制性外，相对过量的AAs增加了AA代谢，刺激谷氨酰胺循环，导致信号通路激活，APC神经元增强。当APC神经元被激活时，它们的谷氨酸能输出首先作用于AMPA受体，向大脑的其他部分发出AA缺乏的信号，从而产生厌食反应。

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.