Molecular Mechanisms of Glycerol Kinase Deficiency

描述（由申请人提供）： 我的长期职业目标是有一个学术职位，我会做基本的 先天性代谢缺陷的科学研究，诊断和治疗患者 遗传疾病的人，教授医学和研究生。我的短期 职业目标是获得一个有指导的助理教授职位 这将使我成为一个独立的物理学家和科学家。 这个应用程序是我从遗传学研究员和临床 教师成为一个独立的物理学家，科学家和初级教师 会员是否研究职业发展计划包括指导和课程工作 在代谢流、动力学分析和成像领域。这些课程 在成像和动力学分析的数学领域， 我需要掌握的关键主题，以成为一名独立的研究人员 在这个领域。我选择在加州大学洛杉矶分校从事这项工作，因为我已经开始了这项工作。 在爱德华·R博士的实验室里进行的研究。B。麦凯布是一名遗传学研究员， 因为加州大学洛杉矶分校在成像方面的资源和声誉，特别是， 功能成像 该提案的重点是了解甘油激酶（GK）的发病机制 缺乏症-一种X连锁的先天性代谢缺陷。GK表达最高 在肝脏中的水平和磷酸化甘油甘油3-磷酸。 然后甘油3-磷酸作为糖酵解途径的底物， 糖原生成、糖原生成和甘油脂的合成，包括 甘油三酯和缩醛磷脂。GK缺乏症（GKD）作为Xp21的一部分发生， 连续基因综合征或孤立的GKD，可能有症状（发作性 代谢和中枢神经系统（CNS）失代偿）或无症状 (only假性高胆固醇血症）。我们调查了孤立的 GKD是由于错义突变引起的，并已显示无相关性 基因型和表现型之间的区别我们的目标是了解GK的表达 以及GKD的发病机制。我们的第一个具体目标是定义GK 启动子和对GK表达重要的转录因子。第二 具体目的是确定个体突变对 通过使用稳定同位素，成像， 在淋巴母细胞样细胞系和GK敲除小鼠中的微阵列研究。更好的 了解这种疾病的过程将提高我们的诊断能力， 治疗这种罕见的代谢紊乱患者，同时让我们了解 更常见的疾病，破坏碳水化合物和脂肪代谢，如 糖尿病的

DESCRIPTION (provided by applicant): My long-term career goal is to have an academic position where I will do basic science research on inborn errors of metabolism, diagnose and treat patients with genetic disorders, and teach medical and graduate students. My short-term career goals are to obtain an assistant professor level position with mentoring that will make me an independent physician-scientist. This application is for my transition from genetics fellow and clinical instructor to become an independent physician-scientist and junior faculty member. The research career development plan includes mentoring and course work in the areas of metabolic flux, kinetics analysis and imaging. The courses are in the areas of the mathematics of imaging and kinetic analysis, and represent critical topics that I will need to master to become an independent researcher in this area. I choose to pursue this work at UCLA as I have already begun this research in the laboratory of Dr. Edward R. B. McCabe as a genetics fellow, and because of the resources and reputation of UCLA in imaging, and, in particular, functional imaging. This proposal focuses on understanding the pathogenesis of glycerol kinase (GK) deficiency - an X-linked inborn error of metabolism. GK is expressed at highest levels in the liver and phosphorylates glycerol to glycerol 3-phosphate. Glycerol 3-phosphate then serves as a substrate for the glycolytic pathway, glycogenesis, gluconeogenesis, and the synthesis of glycerolipids including triglycerides and plasmalogens. GK deficiency (GKD) occurs as part of an Xp21 contiguous gene syndrome or as isolated GKD which may be symptomatic (episodic metabolic and central nervous system (CNS) decompensation) or asymptomatic (only pseudo-hypertriglyceridemia). We have investigated patients with isolated GKD due to missense mutations, and have showed that there is no correlation between genotype and phenotype. Our goal is to understand the expression of GK and the pathogenesis of GKD. Our first specific aim is to define the GK promoter and the transcription factors important for GK expression. The second specific aim is to determine the effect of the individuals' mutations on the metabolic flux in the cell through use of stable isotope, imaging, and microarray studies in lymphoblastoid cell lines and GK knockout mice. A better understanding of this disease process will improve our ability to diagnose and treat patients with this rare metabolic disorder, while giving us insight into more common disorders that disrupt carbohydrate and fat metabolism, such as diabetes mellitus.