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，在那里我将做基础工作 代谢先天疾病的科学研究及对患者的诊疗 患有遗传疾病，并教授医学和研究生。我的短期 职业目标是获得一个有指导的助理教授级别的职位。 这将使我成为一名独立的内科医生兼科学家。 这份申请表是为我从遗传学研究员和临床医生过渡而来的 教师成为独立的内科医生-科学家和初级教员 成员。研究职业发展计划包括指导和课程工作 在代谢流量、动力学分析和成像领域。这些课程包括 在成像和运动分析的数学领域，并代表 成为一名独立研究人员需要掌握的关键话题 在这片区域。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 爱德华·R·B·麦凯布博士作为遗传学研究员在实验室进行的研究，以及 由于加州大学洛杉矶分校在成像领域的资源和声誉，尤其是， 功能成像。 这项建议侧重于了解甘油激酶(GK)的发病机制。 缺乏症--一种X连锁的先天代谢错误。GK的表达水平最高 在肝脏中的水平，并将甘油磷酸化为3-磷酸甘油。 然后，3-磷酸甘油作为糖酵解途径的底物， 糖异生、糖异生和甘油脂的合成，包括 甘油三酯和血浆原。GK缺乏(GKD)是Xp21的一部分 邻近基因综合征或可能有症状的孤立GKD(发作性 代谢和中枢神经系统(CNS)失代偿)或无症状 (只有假性高甘油三酯血症)。我们调查了患有孤立性疾病的患者 GKD是由于错义突变引起的，并已表明与此没有相关性 在基因和表型之间。我们的目标是理解GK的表达 GKD的发病机制。我们的第一个具体目标是定义GK 启动子和转录因子对GK的表达起重要作用。第二 具体目的是确定个体突变对 通过使用稳定的同位素，成像和细胞内的代谢流量 基因芯片在淋巴母细胞系和GK基因敲除小鼠中的研究。更好的 对这一疾病过程的了解将提高我们诊断和 治疗这种罕见的代谢紊乱的患者，同时让我们深入了解 更常见的扰乱碳水化合物和脂肪代谢的疾病，如 糖尿病。

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.