Molecular Mechanisms of Glycerol Kinase Deficiency

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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.