MOLECULAR GENETIC STUDIES OF GLYCEROL KINASE DEFICIENCY

甘油激酶缺陷的分子遗传学研究

• 批准号: 6182018
• 负责人: Edward R B McCabe
• 金额: $ 24.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6182018
• 关键词: artificial chromosomes; chromosome complement; enzyme deficiency; gene deletion mutation; gene expression; gene targeting; genetic markers; genetic recombination; genetically modified animals; genotype; glycerol kinase; human subject; laboratory mouse; linkage mapping; messenger RNA; molecular cloning; molecular pathology; nucleic acid hybridization; nucleic acid probes; phenotype; tissue /cell culture

DESCRIPTION: (Adapted from investigator's abstract) Glycerol kinase deficiency (GKD) may be caused by deletion of the entire GK gene as part of a contiguous gene syndrome, complex GKD, or by intragenic mutations in isolated GKD. Isolated GKD is associated with two different clinical presentations: the symptomatic form with episodic altered central nervous system status with or without hypoglycemia; or the benign form with incidental observation of pseudohypertriglyceridemia. Using the patients with contiguous gene deletions we cloned two of the genes responsible for the complex phenotype, one of which was GK. It is now proposed to investigate the pathogenesis of GKD by examining the hypothesis that GK mutations will have specific and identifiable effects on GK protein expression and/or function and structure that will alter the concentration and flux of metabolic intermediates involved in glycerolipid and energy metabolism. To pursue this hypothesis the following Specific Aims are proposed: (1) To investigate the effects of GK mutations on GK expression, function and structure we will identify intragenic mutations, determine their effects on expression and function, elucidate their structural consequences, and correlate structure with function in the GK protein; and (2) To understand the pathogenesis of symptomatic GKD, we will investigate the concentration and flux of metabolic intermediates in a knockout mouse model, conditionally rescue or moderate the phenotype to permit survival for metabolic investigations, and introduce wild type and mutant GK genes into the knockout mice by viral mediated gene transfer to study the resulting clinical and biochemical phenotypes. In addition to clarifying the fundamental biology of GK and the pathogenesis of GKD, these investigations will provide basic insights into the dynamics of glycerolipid metabolism and potential tools for studies of tumorigenesis, ethanol oxidation and peroxisomal proliferation.

描述：（根据研究者的摘要进行了改编）甘油激酶缺乏症 （GKD）可能是由于整个GK基因的删除而引起的，作为连续的一部分 基因综合征，复杂的GKD或通过分离的GKD中的基因突变。 孤立的GKD与两个不同的临床表现有关： 具有情节性改变中枢神经系统状态的症状形式与或 没有低血糖；或良性形式，偶然观察 假甘油三酸酯血症。使用连续基因缺失的患者 我们克隆了两个负责复杂表型的基因，其中一种 是GK。 现在建议通过检查GKD的发病机理 假设GK突变将对GK具有特定且可识别的影响 蛋白质表达和/或功能和结构将改变 参与甘油脂质和的代谢中间体的浓度和通量 能量代谢。 为了提出这一假设，提出了以下具体目标：（1） 研究GK突变对GK表达，功能和功能的影响 结构我们将确定基因内突变，确定其对 表达和功能，阐明其结构后果并相关 在GK蛋白中具有功能的结构； （2）了解 有症状GKD的发病机理，我们将研究浓度和通量 在敲除鼠标模型中的代谢中间体的，有条件地营救或 调节表型以允许代谢研究生存，并 通过病毒将野生型和突变GK基因引入敲除小鼠 介导的基因转移以研究所得的临床和生化 表型。 除了阐明GK的基本生物学以及 GKD，这些调查将提供有关动态的基本见解 甘油代谢和肿瘤发生研究的潜在工具， 乙醇氧化和过氧化物酶体增殖。