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）表现为消瘦症或恶性营养不良。消瘦是消瘦的特征，而营养不良、水肿、血浆蛋白降低、皮炎、皮肤色素减退、免疫和抗氧化能力受损、神经系统异常和肝脂肪变性是恶性营养不良的额外特征。这些症状的发病机制和康复的最佳饮食仍不清楚。我们认为芳香族氨基酸（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，色氨酸是血清素和烟酸的前体，所以缺乏AAAs可能是夸希奥科病的大多数体征和症状的基础。我们还提出，感染诱导的合成的积极急性期蛋白进一步限制了AAAs的合成其他蛋白质的可用性，因此补充营养转运蛋白（NTPs）和瘦肉组织。稳定同位素示踪方法将被用来测试这些假设在儿童PEM。方案1将确定恶性营养不良和消瘦儿童的AAA和全身蛋白动力学差异。检验的假设是，患有恶性营养不良症而非消瘦症的儿童由于蛋白质分解受损而释放减少，因此AAAs的可用性降低。方案#2将确定消瘦型恶性营养不良儿童在治疗期间的AAA需求，以检验治疗性饮食提供的AAA量对于蛋白质的最佳合成是有限的这一假设。方案#3将确定补充AAAs或丙氨酸对患有恶性营养不良症的儿童的蛋白质动力学和所选NTP合成的影响。还将监测精神状态、食欲和皮肤变化。测试的假设是，1）在营养恢复期间提供足够量的AAA将刺激NTP和全身蛋白质合成速率到比丙氨酸对照更大的程度，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毛发出现所需的时间。这项研究可以解释三种称为芳香族氨基酸的特殊化合物的短缺是否是患营养不良型夸希奥科病的儿童的严重疾病和高死亡率的原因，以及在治疗饮食中提供足够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.