Glycogen is a branctied storage polymer of glucose that serves as an energy reserve in many cell types. In absolute terms, liver and skeletal muscle house the largest glycogen deposits in mammals and are critical to whole body glucose metabolism. The overall goal of this proposal is to improve understanding of the mechanism and control of glycogen synthesis, its relevance to whole body glucose metabolism and its impairment in metabolic diseases like diabetes and and certain glycogen storage diseases. Glycogen is synthesized from UDP-glucose by the enzyme glycogen synthase.
Aim (i) Role of genethonin 1 (Stbd1) in glycogen metabolism. We have found a new protein, genethonin 1, that binds to glycogen and may function to target glycogen to lysosomes. We will investigate the role of genethonin 1 in this pathway.
Aim (ii). Glycogen in mouse models of glucose homeostasis. We will study genetically modified mice as a means to assess glycogen function and to assess its role in different tissues of the body. We will continue analysis of mice lacking liver glycogen (LGSKO) and will use Cre-Lox techniques to eliminate glycogen accumulation in muscle, heart, beta cells and brain by tissue specific disruption of the glycogen synthase gene, Gys1.
Aim (iii) UDP-glucose pyrophosphatase (UGPPase). This enzyme hydrolyzes UDP-glucose and thus may impact glycogen metabolism. Our work will combine transgenic overexpression with gene knockout in mice to evaluate its importance.
Aim (iv) Phosphoglucosylation of proteins and potential role in metabolic control. In the course of our work, we have found evidence for a novel post-translational modification of proteins whereby glucose-phosphate is transferred from UDP-glucose to acceptor proteins. We will explore this phenomenon, seeking to identify the modifying enzyme(s), to understand the effect of the modification on protein function and to establish its physiological relevance.
Most of the proposal addresses glycogen which plays an important role in the energy metabolism of the body. Understanding how glycogen deposits in different tissues impact physiological parameters such as blood glucose homeostasis and exercise capacity is therefore of considerable significance. Numerous disease states affect or are affected by glycogen metabolism, including diabetes and glycogen storage diseases. The last aim seeks to define and evaluate a newly discovered covalent modification of proteins which, based on its occurence on a number of metabolic enzymes, may also have an influence on metabolism.
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