NUTRITION IN RETT SYNDROME

RETT 综合征的营养

• 批准号: 6306259
• 负责人: KATHLEEN J MOTIL
• 金额: $ 3.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6306259
• 关键词: Rett syndrome; aminoacid metabolism; body composition; calcium metabolism; clinical research; dietary aminoacid; dietary calcium; female; gastrointestinal absorption /transport; human subject; mass spectrometry; medical complication; nutrient intake activity; nutrient requirement; nutrition related tag; photon absorptiometry; protein biosynthesis; protein metabolism; radioimmunoassay; urea

The OBJECTIVE of this proposal is to characterize the components of protein and calcium metabolism that are altered and to estimate their contribution to the overall protein and calcium requirements of RS girls. The SPECIFIC AIMS for this project are:1)to determine if rates of body protein degradation, leucine oxidation, and urea production are higher and body protein synthesis, net protein retention, and the splanchnic extraction of lysine are lower in RS than in healthy girls, using a primed, constant infusion of [1-13C]leucine, [d4,4,5,5]lysine, and [15N2]urea to calculate rates of whole body protein synthesis, degradation, leucine oxidation, net protein retention, the splanchnic extraction of lysine, and urea production; 2)to determine if fractional rates of intestinal calcium absorption are lower and rates of diet-and bone-derived urinary calcium excretion are higher in RS than in healthy girls, using a single bolus dose of 42Ca and 46Ca to calculate fractional rates of calcium absorption, total absorption, net balance, and diet- and bone-derived urinary calcium; 3)to determine if serum insulin, IGF-1, growth hormone, and osteocalcin levels are lower and urinary cortisol outputs are higher in RS than in healthy girls. To test our hypotheses, two groups of SUBJECTS, RS and healthy girls, will be studied during controlled dietary conditions. METHODS: Body protein and calcium metabolism will be examined using state-of-the-art stable isotope mass spectrometry techniques. Rates of body protein synthesis, degradation, net retention, and urea production will be determined using primed, constant infusions of [1-13C]leucine, [d4,4,5,5]lysine, and [15N2]urea. Rates of intestinal absorption and diet- or bone-derived urinary losses of calcium will be determined by intravenous/oral single bolus doses of 42Ca and 46Ca. Body composition will be determined using whole body potassium (40K) counting and duel-energy x-ray absorptiometry. Hormone profiles (plasma insulin, IGF-1, growth hormone, osteocalcin, and urinary cortisol) will be measured using radioimmunoassay techniques. Analysis of covariance and linear regression will be used to detect differences in the outcome variables of body protein and calcium metabolism and hormone profiles between RS and healthy girls. PROGRESS: To date, we studied three RS girls, two who were fed via gastrostomy button and one who fed orally. The results of the protein and calcium metabolic studies of RS girls are summarized below and are compared with measurements of body protein metabolism in children with Crohn disease. The major points to be made from these observations are: 1)In the postabsorptive state, rates of endogenous body protein degradation exceeded rates of body protein synthesis, such that net protein retention was negative and reflected the expected catabolic state during postabsorptive conditions. 2)In the fed state, leucine flux was 2.5-fold greater than that obtained in the postabsorptive state. However, this difference was explained entirely by the intake of dietary leucine, resulting in no net difference of endogenous body protein degradation between the postabsorptive and fed state. 3)In the fed state, rates of endogenous body protein degradation approximated rates of body protein synthesis, such that net protein retention was neutral and reflected the reversal of the catabolic state with feeding. 4)In the fed state, rates of body protein synthesis and oxidation were 2- to 3-fold greater than those obtained in the postabsorptive state; nevertheless, protein oxidation, as a proportion of total flux, was disproportionately greater (2-fold) than the proportion of flux represented by protein synthesis. 5)In the fed state, rates of urea production were double those obtained in the postabsorptive state. Assuming that 75% of all urea nitrogen was excreted, dietary nitrogen was utilized with 79% efficiency, a value that compared favorably with that of healthy children. 6)When the variables of body protein metabolism of RS girls were compared with those of children with Crohn disease, the striking features were the disproportionately greater rates of endogenous protein breakdown, as well as the increased rates of protein synthesis and oxidation, in the RS girls. More importantly, as a proportion of total flux, endogenous body protein degradation was 3-fold greater, body protein synthesis was 25% lower, and protein oxidation was 25% higher in RS girls than in children with Crohn disease. 7)The fractional absorption of dietary calcium and vitamin D and parathyroid hormone levels were normal in RS girls. The SIGNIFICANCE of these preliminary observations is that muscle wasting in RS girls may be the consequence of a heightened catabolic state in which rates of endogenous body protein degradation markedly exceed rates of body protein synthesis. Feeding does not suppress the high rates of endogenous body protein degradation. The disproportionately high rates of protein oxidation, particularly as a proportion of total flux, also may account for reduced protein availability and further aggravate muscle wasting. In contrast, bone demineralization in RS girls does not appear to be the result of a defect in the intestinal absorption of dietary calcium nor a deficiency of vitamin D dietary intake or its metabolism. These preliminary results are important because they provide further insight into the metabolic mechanisms that lead to muscle wasting and bone demineralization in RS girls and may result in more rational therapeutic strategies that enhance the functional outcome and quality of life in RS girls with growth arrest. If these preliminary findings are consistently present in RS girls, these abnormalities in body protein metabolism may be responsive to dietary or hormonal intervention. Further studies will be necessary to examine the dietary and/or hormonal factors that regulate body protein metabolism in RS girls.

该提案的目的是描述以下内容的组成部分： 改变的蛋白质和钙代谢并估计它们的 对 RS 总体蛋白质和钙需求的贡献 女孩们。 该项目的具体目标是：1）确定费率 体内蛋白质降解、亮氨酸氧化和尿素生成的过程 更高的身体蛋白质合成、净蛋白质保留以及 RS 中赖氨酸的内脏提取量低于健康女孩， 使用已引发的持续输注[1-13C]亮氨酸、[d4,4,5,5]赖氨酸， 和[15N2]尿素计算全身蛋白质合成率， 降解、亮氨酸氧化、净蛋白质保留、内脏 赖氨酸的提取和尿素的生产； 2）判断是否为小数 肠道钙吸收率较低，饮食和钙吸收率较低 RS 中骨源性尿钙排泄量高于健康人 女孩，使用单次推注剂量 42Ca 和 46Ca 来计算 钙吸收分数率、总吸收率、净平衡、 以及饮食和骨源性尿钙； 3) 判断血清是否 胰岛素、IGF-1、生长激素和骨钙素水平较低， RS 患者的尿皮质醇排出量高于健康女孩。 到 检验我们的假设，两组受试者，RS 和健康女孩，将 在受控饮食条件下进行研究。 方法：身体蛋白质 钙代谢将使用最先进的稳定系统进行检查 同位素质谱技术。身体蛋白质合成率， 降解、净保留和尿素产量将通过以下方式确定 [1-13C]亮氨酸、[d4,4,5,5]赖氨酸和持续输注 [15N2]尿素。肠道吸收率和饮食或骨吸收率 尿钙损失将通过静脉/口服单次测定 42Ca和46Ca的推注剂量。身体成分将通过以下方式确定 全身钾（40K）计数和双能X射线 吸收测定法。激素概况（血浆胰岛素、IGF-1、生长 激素、骨钙素和尿皮质醇）将使用测量 放射免疫分析技术。协方差和线性分析 回归将用于检测结果变量的差异 RS 之间的身体蛋白质和钙代谢以及激素概况 和健康的女孩。 进展：迄今为止，我们研究了三名 RS 女孩，其中两名 一组通过胃造口按钮喂养，另一组通过口服喂养。结果 RS女孩的蛋白质和钙代谢研究总结 下面并与体内蛋白质代谢的测量结果进行比较 患有克罗恩病的儿童。从这些要点中可以看出 观察结果是： 1）在吸收后状态，内源性比率 身体蛋白质的降解速度超过了身体蛋白质合成的速度，例如 净蛋白质保留为负，反映了预期 吸收后条件下的分解代谢状态。 2）在美联储状态下， 亮氨酸通量是 2.5 倍 吸收后状态。然而，这种差异已被完全解释 通过饮食亮氨酸的摄入，导致没有净差异 吸收后和进食之间的内源性体内蛋白质降解 状态。 3）在进食状态下，内源性体内蛋白质降解率 身体蛋白质合成的近似速率，使得净蛋白质 保留是中性的，反映了分解代谢状态的逆转 与喂养。 4）在进食状态下，体内蛋白质合成率和 氧化程度比实验中获得的氧化程度高 2 至 3 倍 吸收后状态；尽管如此，蛋白质氧化，作为一个比例 的总通量，不成比例地大于（2倍） 由蛋白质合成代表的通量比例。 5）在美联储状态下， 尿素生产率是当年的两倍 吸收后状态。假设所有尿素氮的 75% 排出体外，膳食氮的利用效率为 79%，这是一个数值 与健康儿童相比，效果更好。 6）当 RS女孩体内蛋白质代谢变量与 克罗恩病儿童的显着特征是 内源性蛋白质分解率不成比例地更高， 以及蛋白质合成和氧化速率的增加 RS 女孩。更重要的是，作为总通量的一部分，内生 体内蛋白质降解量增加了 3 倍，体内蛋白质合成量增加了 3 倍 RS 女孩比对照组女孩低 25%，蛋白质氧化高 25% 患有克罗恩病的儿童。 7）膳食吸收分数 RS 患者的钙、维生素 D 和甲状旁腺激素水平正常 女孩们。这些初步观察的意义在于，肌肉 RS女孩的消瘦可能是分解代谢加剧的结果 内源性体内蛋白质降解率显着下降的状态 超过体内蛋白质合成的速率。喂食不会抑制 内源性体内蛋白质降解率高。这 蛋白质氧化率不成比例地高，特别是作为 总通量的比例，也可能是蛋白质减少的原因 可用性并进一步加剧肌肉萎缩。相比之下，骨 RS 女孩的脱矿质似乎并不是以下原因造成的： 肠道吸收膳食钙的缺陷也不是缺乏 维生素 D 膳食摄入量或其代谢的影响。这些初步结果 很重要，因为它们提供了对代谢的进一步了解 导致 RS 肌肉萎缩和骨脱矿的机制 女孩，可能会导致更合理的治疗策略 提高 RS 女孩的功能结果和生活质量 生长停滞。如果这些初步发现始终存在 在RS女孩中，身体蛋白质代谢的这些异常可能是 对饮食或激素干预有反应。进一步的研究将是 有必要检查调节饮食和/或激素的因素 RS女孩体内蛋白质代谢。