Glutathione Homeostasis & Oxidant Damage in Kwashiorkor

描述（由申请人提供）：严重儿童营养不良（SCU）表现为消瘦症、恶性营养不良症或消瘦-恶性营养不良症。虽然消瘦是所有综合征的特征，但在恶性营养不良和消瘦性恶性营养不良（水肿性SCU）中，总体水肿、血浆蛋白降低、皮肤炎、免疫和抗氧化能力受损是导致发病率增加和恢复较慢的附加特征。我们发现，与消瘦儿童相比，水肿性SCU儿童半胱氨酸及其前体蛋氨酸的通量较慢，因为蛋白质分解较慢，释放量减少。我们认为，这两种含硫氨基酸（SAA）的可用性降低有助于某些临床特征的发病机制，因此，水肿性SCU儿童的恢复较慢。研究将在6-18个月内进行。老年儿童与SCU，以实现以下具体目标。具体目标#1将确定水肿性和非水肿性SCU儿童在代谢稳定和康复早期追赶生长阶段的SAA要求。检验的假设：在急性营养不良状态下，相对于非水肿性SCU儿童，水肿性SCU儿童的蛋白质分解较慢，导致SAA可用性降低。因此，在水肿性SCU儿童中，用于补充代谢能力和合成代谢驱动的膳食SAA供应将更大。具体目标#2将确定水肿性和非水肿性SCU儿童的膳食SAA的内脏提取。检验的假设：因为半胱氨酸是GI粘蛋白和粘膜谷胱甘肽（GSH）的主要组分，所以内源性SAA产生的减少意味着在患有水肿性SCU的儿童中，膳食SAA的肠道需求（因此内脏提取）将更大。具体目标#3 a和B将确定在患有水肿性SCU的年龄和性别匹配的儿童组中，用SAA或丙氨酸的混合物（对照）进行膳食补充对小肠结构、完整性和功能、皮肤表皮蛋白合成、皮肤损伤消退速率和免疫能力恢复的影响。检验的假设：在康复的早期阶段，补充具有足够量的SAA的复苏饮食将刺激肠粘膜和消化酶蛋白质、粘膜GSH和皮肤表皮蛋白质的合成速率至比丙氨酸对照更大的程度，从而更早地恢复小肠结构和功能以及皮肤病变的消退。类似地，GSH合成的更快正常化将促进免疫功能的更早恢复。这项研究可以解释两种称为硫氨基酸的特殊化合物的短缺是否是恶性营养不良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数量的这些化合物是否会加速恢复。

DESCRIPTION (provided by applicant): Severe childhood under nutrition (SCU) presents either as marasmus, kwashiorkor, or marasmic- kwashiorkor. While wasting characterizes all syndromes, in kwashiorkor and marasmic-kwashiorkor (edematous SCU), gross edema, lower plasma proteins, flaky paint dermatitis, impaired immune and anti- oxidant capacities, are among additional features that contribute to an increased morbidity and slower recovery. We have found that compared to children with marasmus, children with edematous SCU have slower fluxes of cysteine and its precursor methionine because of decreased release from a slower protein breakdown. We propose that decreased availability of these two sulfur amino acids (SAAs) contribute to the pathogenesis of certain clinical features and hence, the slower recovery of children with edematous SCU. Studies will be performed in 6-18 mo. old children with SCU to achieve the following specific aims. Specific aim #1 will determine the SAA requirements of children with edematous and non-edematous SCU during the metabolic stabilization and early catch-up growth phases of rehabilitation. Hypothesis tested: In the acutely malnourished state, a slower protein breakdown in children with edematous SCU relative to those with non- edematous SCU results in decreased availability of SAAs. Hence, dietary SAAs supply for replenishment of metabolic capacity and anabolic drive will be greater in children with edematous SCU. Specific aim #2 will determine the splanchnic extraction of dietary SAAs in children with edematous and non-edematous SCU. Hypothesis tested: Because cysteine is a major component of Gl mucins and mucosal glutathione (GSH), a reduction in endogenous SAA production means that the gut requirement, hence splanchnic extraction of dietary SAAs will be greater in children with edematous SCU. Specific aim #3 a&b will determine the effect of dietary supplementation with either a mixture of SAAs or alanine (controls) on small intestine structure, integrity and function, skin epidermal protein synthesis, rate of resolution of skin lesions and recovery of immune capacity in groups of age- and gender-matched children with edematous SCU. Hypotheses tested: During the early phase of rehabilitation, supplementation of the resuscitative diet with adequate amounts of SAAs will stimulate synthesis rates of gut mucosal and digestive enzymes proteins, mucosal GSH and skin epidermal protein to a greater extent than in alanine controls, thereby restoring small intestine structure, and function and resolution of skin lesions earlier. Similarly, faster normalization of GSH synthesis will facilitate earlier restoration of immune function. This research may explain whether a shortage of two special compounds called sulfur 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.