Defining the mechanisms of the glycophagy shunt and its role in metabolism

Glucose metabolism is tightly regulated and has a central role in cell biology, while dysregulated glucose metabolism is a common occurrence in various metabolic diseases such as cancer, heart disease, diabetes, and brain disease. Most glucose that enters a cell is shuttled through glycogen prior to re-entering the glycolytic pathway, in a cycle known as the glycogen shunt. An important aspect of the glycogen shunt is glycogen degradation, a compartment specific process that occurs either within the cytosol or lysosomes. The enzymes glycogen debranching enzyme and glycogen phosphorylase mediate glycogenolysis in the cytosol, a process that has been extensively studied and is well characterized in metabolism. However, the contribution of glycogen autophagy (glycophagy) to metabolism and the glycogen shunt has not been characterized. Given the importance of glycogen metabolism in health and disease and the lack of fundamental knowledge of glycophagy, the overall vision for my lab over the next five years is to better decipher the mechanisms of glycophagy and its contribution to the glycogen shunt and cell metabolism. We will utilize novel genetically modified cells and mice that we have developed to study glycophagy. Additionally, we will establish new innovative tools that can be leveraged to gain a better grasp of glycophagy in cell biology. The freedom and flexibility offered by the R35 grant mechanism will allow us to develop and employ these innovative tools that will enable influential discoveries in glycophagy research. This fundamental understanding of glycophagy in metabolism that this work will provide will benefit a broad array of genetic and metabolic diseases where glycogen metabolism is involved, such as Pompe disease, Danon disease, cancer, heart disease, diabetes, and brain disease.