NUTRITION IN RETT SYNDROME

RETT 综合征的营养

• 批准号: 6278025
• 负责人: KATHLEEN J MOTIL
• 金额: $ 2.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6278025
• 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.

该提议的目的是表征 蛋白质和钙代谢发生了变化并估算其 对RS的整体蛋白质和钙需求的贡献 女孩们。 该项目的具体目的是：1）确定是否比率 人体蛋白质降解，亮氨酸氧化和尿素的产生是 更高和身体蛋白质的合成，净蛋白保留和 赖氨酸的诊断提取的rs比健康女孩低， 使用[1-13c]亮氨酸的启动，恒定输注，[D4,4,5,5]赖氨酸， 和[15n2]尿素以计算全身蛋白质合成的速率， 降解，亮氨酸氧化，净蛋白保留，隐质 提取赖氨酸和尿素的产生； 2）确定是否要分数 肠钙吸收率较低，饮食速率和 骨源性尿钙排泄的RS高于健康 女孩，使用42CA和46CA的单一推注剂量计算 钙吸收的分数，总吸收，净值， 以及饮食和骨骼衍生的尿钙； 3）确定是否血清 胰岛素，IGF-1，生长激素和骨钙素水平较低，并且 尿皮质醇输出的RS高于健康女孩。 到 测试我们的假设，两组受试者，RS和健康的女孩， 在受控饮食条件下进行研究。 方法：身体蛋白质 和钙代谢将使用最先进的稳定检查 同位素质谱技术。身体蛋白质的速率， 降解，净保留和尿素生产将使用 [1-13c]亮氨酸，[D4,4,5,5]赖氨酸和 [15n2]尿素。肠吸收和饮食或骨骼的速率 钙的尿液损失将由静脉/口服单一确定 推注剂量为42CA和46CA。身体成分将使用 全身钾（40k）计数和决斗 - 能源X射线 吸收法。激素谱（血浆胰岛素，IGF-1，生长 将使用激素，骨钙素和尿皮质醇）使用 放射免疫测定技术。协方差分析 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和激素谱 和健康的女孩。 进度：迄今为止，我们研究了三个RS女孩，两个 通过胃造口术按钮喂食的人，一个口口感的人。结果 RS女孩的蛋白质和钙代谢研究总结了 以下并与人体蛋白质代谢的测量进行比较 克罗恩病的孩子。这些要提出的要点 观察值为：1）在降后状态，内源性速率 人体蛋白质降解超过了人体蛋白质的合成速率， 净蛋白保留率为阴性，并反映了预期的 在吸收后条件下分解代谢状态。 2）在美联储州， 亮氨酸通量比在 释放状态。但是，完全解释了这种差异 通过饮食亮氨酸的摄入，没有净差异 后吸收和喂养之间的内源性身体蛋白质降解 状态。 3）在美联储状态，内源性体蛋白降解速率 近似人体蛋白质合成速率，使得净蛋白 保留是中性的，反映了分解代谢状态的逆转 喂食。 4）在美联储状态下，身体蛋白质的速率和 氧化比在 后吸收状态；然而，蛋白质氧化为一定比例 总通量的不成比例大（2倍） 蛋白质合成代表的通量的比例。 5）在美联储州， 尿素生产率是在 释放状态。假设所有尿素氮中有75％是 排泄的，饮食氮的效率为79％，价值 与健康的孩子相比，这比较有利。 6）当 将RS女孩的身体蛋白质代谢变量与 那些患有克罗恩病的儿童，引人注目的特征是 内源性蛋白质分解的比例不成比例，因为 以及蛋白质合成和氧化速率的增加，在 RS女孩。更重要的是，作为总通量，内源性的一部分 人体蛋白质降解大3倍，体蛋白合成为 RS女孩低25％，蛋白质氧化高25％ 克罗恩病的孩子。 7）饮食的分数吸收 钙和维生素D和甲状旁腺激素水平正常 女孩们。这些初步观察的意义是肌肉 浪费RS女孩可能是分解代谢增强的结果 状态在哪种内源性蛋白质降解率明显降解速率 超过人体蛋白质合成的速率。喂养不会抑制 内源性蛋白质降解的高速率。这 蛋白质氧化速率不成比例，特别是作为一种 总通量的比例，也可能解释蛋白质的降低 可用性并进一步加剧肌肉浪费。相反，骨头 RS女孩中的矿化似乎并不是 饮食钙的肠道吸收缺陷或缺乏 维生素D饮食摄入或其代谢。这些初步结果 很重要，因为它们可以进一步了解代谢 导致肌肉浪费和骨骼脱矿的机制 女孩，可能会导致更合理的治疗策略 增强RS女孩的功能结果和生活质量 增长逮捕。如果这些初步发现始终存在 在RS女孩中，体内蛋白质代谢中的这些异常可能是 对饮食或荷尔蒙干预的反应。进一步的研究将是 检查调节的饮食和/或激素因素所必需的 RS女孩的身体蛋白质代谢。