NICHD CLINICAL INVESTIGATOR AWARD--PEDIATRICS

NICHD 临床研究者奖——儿科

• 批准号: 3081236
• 负责人: RICHARD Ian KELLEY
• 金额: $ 6.42万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-30 至 1985-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3081236
• 关键词: UTP hexose 1 phosphate uridylyltransferase; centrifugation; chemical structure function; diet therapy; drug administration routes; electrofocusing; galactose; galactosemias; gas chromatography; high performance liquid chromatography; isozymes; liver disorder; mass spectrometry; mental retardation

Classical galactosemia, the clinical syndrome of failure to thrive, cataracts, galactosuria, liver disease and mental retardation, is most often caused by a severe deficiency, but not usually total absence of the enzyme galactose-1-phosphate uridyltransferase (GALT). In addition to eliminating dietary galactose in the treatment of galatosemia, there are clinical and theoretical arguments for augmenting residual GALT activity for protection against mental retardation or more subtle cumulative toxicities. This research proposes to study the molecular basis for two recently identified methods of increasing GALT activity: perfusion of suckling rat liver with galactose and folic acid treatment of suckling rats. The molecular mechanisms responsible for stimulated GALT activity will be examined by the analysis of in tissue specific microheterogeneity of GALT. This will involve 1) defining the variety of tissue specificity of GALT isozymes by isoelectric focusing; 2) following quantitative and qualitative changes in the GALT isozyme patterns in the folate treated rat and in the in situ liver perfusion with carbohydrate solutions; 3) determining the specific post-translational modifications of GALT using a variety of chemical and enzymatic approaches; 4) purifying selected GALT isozymes for detailed kinetic and chemical studies. Together these studies will add to our knowledge of the molecular biology of GALT and mechanism for the specific enhancement of GALT activity in the treatment of galactosemia.

典型的半乳糖血症，一种发育不良的临床综合征， 白内障、糖尿、肝病和智力迟钝， 通常由严重缺乏引起，但通常不是完全缺乏 半乳糖-1-磷酸尿苷酰转移酶（GALT）。 除了 消除饮食中的半乳糖在治疗半乳糖血症，有 增加残余GALT活性的临床和理论论据 为了防止智力迟钝或更微妙的累积 毒性 这项研究提出了研究两个分子基础 最近确定的增加GALT活性的方法：灌注 用半乳糖和叶酸处理乳鼠肝脏 大鼠 刺激GALT活性的分子机制 将通过组织特异性微异质性分析进行检查 关于GALT 这将涉及1）定义组织特异性的多样性 GALT同工酶的等电聚焦; 2）定量和 叶酸处理大鼠GALT同工酶谱的质的变化 和在原位肝脏灌注与碳水化合物溶液; 3） 使用免疫组织化学方法测定GALT的特异性翻译后修饰， 各种化学和酶法; 4）纯化选定的GALT 用于详细动力学和化学研究的同工酶。 这些研究将共同增加我们的分子生物学知识 GALT的活性及其特异性增强GALT活性的机制 半乳糖血症的治疗。