Glycerol Kinase Deficiency as a Model to Understand Met*

甘油激酶缺乏症作为了解蛋氨酸的模型*

基本信息

批准号：
6910687
负责人：
Katrina M Dipple
金额：
$ 29.96万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term objectives of these investigations are to understand the cellular mechanisms of how a single gene disorder (glycerol kinase deficiency) causes a complex phenotypic disease. Glycerol kinase (GK) catalyzes the phosphorylation of glycerol into glycerol 3-phosphate and is at the interface of glucose and fat metabolism. Glycerol kinase deficiency (GKD) is an X-linked disorder of metabolism that is due to mutations and/or deletions of the glycerol kinase gene (GK). Patients with GKD are phenotypically either symptomatic or asymptomatic. Our initial work on glycerol kinase deficiency has shown that there is no way to predict which patients will be symptomatic and which will be asymptomatic by GK activity or the location of the mutation in a model of the three dimensional structure of the protein. We hypothesize that it is the interaction of GK mutations with additional genetic and environmental influences on metabolic flux (other enzymes in related pathways and levels of critical intermediates) that are important to understand the pathogenesis of this disorder. The goals of this proposal are to understand better the complex interactions within the cell and how perturbations of an individual enzyme (GK) affects the other pathways and gene expression to result in the physiological changes seen in the whole animal. Our first Specific Aim (Task 1) is to characterize the metabolic pathways relating to GK and how they are changed in GKD using lymphoblastoid cells lines from the individuals with GKD as well as normal individuals. Metabolome analysis, flux analysis, and transcriptome analysis will allow us to investigate the effect of the mutations with varying levels of GK activity in the context of the individuals' genetic background. We will then investigate the effect of these mutations in liver and kidney cell lines as these tissues have the highest level of GK expression and will allow us to investigate the role of the GK mutations within the context of identical genetic background. Results of these studies will allow us to perform metabolome, flux, and transcriptome analysis in the whole animal model using the glycerol kinase knock-out (gyk k/o) mouse (Specific Aim/Task 2). These studies will provide a model system to understand the complex nature of genetic disorders and eventually help in treatment of such disorders.

描述（由申请人提供）：这些研究的长期目标是了解单个基因疾病（甘油激酶缺乏症）如何引起复杂的表型疾病的细胞机制。甘油激酶（GK）催化甘油在3-磷酸甘油中的磷酸化，并处于葡萄糖和脂肪代谢的界面。甘油激酶缺乏症（GKD）是一种X连锁的代谢疾病，是由于甘油激酶基因（GK）的突变和/或缺失引起的。 GKD患者在表型上是有症状的或无症状的。我们在甘油激酶缺乏症上的最初工作表明，无法预测哪些患者是有症状的，哪些患者在GK活性或突变的位置无症状或在蛋白质三维结构的模型中的位置。我们假设是GK突变与对代谢通量的其他遗传和环境影响（相关途径和关键中间体水平的其他酶）的相互作用对于了解这种疾病的发病机理很重要。该提案的目标是更好地理解细胞内的复杂相互作用，以及单个酶（GK）的扰动如何影响其他途径和基因表达，从而导致整个动物的生理变化。我们的第一个具体目标（任务1）是表征与GK的代谢途径以及它们在GKD中使用来自GKD和正常个体的个体的淋巴母细胞细胞在GKD中的变化。代谢组分析，通量分析和转录组分析将使我们能够在个体的遗传背景下研究具有不同水平GK活性的突变的效果。然后，我们将研究这些突变在肝脏和肾细胞系中的作用，因为这些组织具有最高水平的GK表达，并将使我们能够研究GK突变在相同的遗传背景背景下的作用。这些研究的结果将使我们能够使用甘油激酶敲除（GYK K/O）小鼠在整个动物模型中进行代谢组，通量和转录组分析（特定的AIM/任务2）。这些研究将提供一个模型系统，以了解遗传疾病的复杂性质，并最终有助于治疗此类疾病。