Aromatic amino acid metabolism in the pathogenesis of kwashiorkor

描述（由申请人提供）：蛋白质能量营养不良（PEM）表现为消瘦或营养不良。消瘦是消瘦症的特征，而在消瘦症中，厌食症、水肿、低血浆蛋白、皮炎、皮肤色素沉着、免疫和抗氧化能力受损、神经异常和肝脂肪变性是附加特征。这些症状的发病机制和康复的最佳饮食仍不清楚。我们认为芳香氨基酸（AAAs）的供应减少是一个因素。因为苯丙氨酸和酪氨酸是多巴胺、黑色素和儿茶酚胺的前体，色氨酸是5 -羟色胺和烟酸的前体，缺乏AAAs可能是营养不良的大部分症状和体征的基础。我们还提出，感染诱导的阳性急性期蛋白合成进一步限制了AAAs合成其他蛋白质的可用性，从而补充了营养转运蛋白（NTPs）和瘦组织。稳定同位素示踪方法将用于在PEM患儿中检验这些假设。方案1将确定夸希奥尔克和消瘦症患儿的AAA和全身蛋白动力学的差异。经检验的假设是，患有夸希奥尔克病而非消瘦症的儿童，由于受损的蛋白质分解释放减少，AAAs的可用性降低。方案#2将确定消瘦-夸希奥尔克尔儿童在治疗期间的AAA需求，以检验治疗性饮食提供的AAA数量是有限的，以达到最佳蛋白质合成的假设。方案#3将确定补充AAAs或丙氨酸对营养不良儿童蛋白质动力学和选定ntp合成的影响。精神状态、食欲和皮肤变化也将被监测。测试的假设是，1)在营养康复期间提供足够量的AAA将比丙氨酸对照组更大程度地刺激ntp和全身蛋白质合成率，2)AAA补充剂将缩短厌食症和精神异常消失以及正常色素皮肤和头发出现的时间。这项研究或许可以解释，是否缺乏三种叫做芳香氨基酸的特殊化合物是导致患有夸希奥尔科营养不良的儿童严重疾病和高死亡率的原因，以及在治疗饮食中提供足量的这些化合物是否会加速这种情况的恢复。

DESCRIPTION (provided by applicant): Protein-energy malnutrition (PEM) presents with marasmus or kwashiorkor. While wasting characterizes marasmus, in kwashiorkor, anorexia, edema, lower plasma proteins, dermatitis, hypopigmented skin, impaired immune and anti-oxidant capacities, neurological abnormalities, and hepatic steatosis are additional features. The pathogenesis of these signs, and optimal diets for rehabilitation remain unclear. We propose that decreased supply of aromatic amino acids (AAAs) is a factor. Because phenylalanine and tyrosine are precursors for dopamine, melanin and the catecholamines, and tryptophan is the precursor of serotonin and niacin, a shortage of the AAAs may underlie most of the signs and symptoms of kwashiorkor. We also propose that infection-induced synthesis of positive acute phase proteins further limits the availability of AAAs for synthesis of other proteins, hence replenishment of nutrient transport proteins (NTPs) and lean tissues. Stable isotope tracer methods will be used to test these hypotheses in children with PEM. Protocol #1 will determine differences in AAA and whole body protein kinetics in children with kwashiorkor and marasmus. The hypothesis tested is that children with kwashiorkor but not marasmus, have decreased availability of the AAAs because of decreased release from an impaired protein breakdown. Protocol #2 will determine the AAA requirements of children with marasmic-kwashiorkor during treatment to test the hypothesis that the amount of AAAs supplied by the therapeutic diets is limited for optimal synthesis of proteins. Protocol #3 will determine the effect of supplementation with either AAAs or alanine on protein kinetics and the synthesis of selected NTPs in children with kwashiorkor. Mental state, appetite and skin changes will also be monitored. The hypotheses tested are, 1) providing adequate amounts of AAAs during nutritional rehabilitation will stimulate NTPs and whole body protein synthesis rates to a greater extent than in alanine controls, 2) AAA supplements will shorten the time taken for anorexia and mental abnormalities to disappear and for normal pigmented skin and hair to appear. This research may explain whether a shortage of three special compounds called aromatic amino acids is responsible for the severe illness and high death rate of children with the kwashiorkor type of malnutrition and whether supplying adequate amounts of these compounds in the treatment diet will speed up recovery from this condition.