Brain Signaling of Essential Amino Acid Deficiency

必需氨基酸缺乏的大脑信号传导

• 批准号: 6844736
• 负责人: DOROTHY W GIETZEN
• 金额: $ 27.22万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844736
• 关键词: AMPA receptors; biological signal transduction; brain; dietary aminoacid; glutamates; glutamine; high performance liquid chromatography; immunocytochemistry; laboratory rat; neurons; nutrition; nutrition related tag; tissue /cell culture; western blottings

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.

说明(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都是必不可少的。由于氨基酸没有储存池，因此必需的氨基酸(IAA)缺乏症可能会迅速发生，特别是如果已经存在轻度蛋白质缺乏症的话。IAA缺乏症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，由于IAA失衡导致的生长减慢实际上次于食物摄入量的减少，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，尤其是“健康食品”爱好者、节食者和运动员可能会使用，IAA失衡应该被认为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人也可能遭受IAA比例失调，这可能会影响他们的恢复。该实验室工作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。我们正在用一种描述良好的营养模型来研究这些机制，该模型使用喂食AA不平衡饮食(IMB)的大鼠。我们最近的工作表明，对IMB做出反应的行为(进食率)的变化发生在喂食的前12分钟内。在这段时间内，我们发现APC中的谷氨酰胺和谷氨酸增加。体外快速变化包括信号转导通路的激活和AA转运体的动员。基于对该模型的了解，我们提出了以下具体目标：1)识别APC中IAA缺乏的初始代谢信号(S)；2)识别由特定目标1中识别的代谢信号激活的信号转导通路；以及3)识别APC中信号IAA缺乏的谷氨酸能输出细胞的激活机制。我们假设：相对过量的AAs增加了AA的代谢，刺激了谷氨酰胺循环，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，它们的谷氨酸能输出首先作用于AMPA受体，向大脑其他部分发出AA缺乏的信号，以进行厌食反应。