Deciphering the Role of Endoplasmic Reticulum Structure and Function in Metabolic Regulation

About This Grant

Project Summary / Abstract Cells optimize their functional capacity in response to extracellular signals to meet metabolic demands and maintain cellular and organism-level homeostasis. Endoplasmic reticulum (ER) is a central hub for protein folding, trafficking, lipid synthesis and secretion. ER also regulates the function of other organelles by exchanging ions and other hydrophobic molecules through inter- organelle contact sites. The structure of the ER is highly dynamic with specialized subdomains such as ER sheets, tubules, 3-way junctions and exit sites. ER exhibits complex architectural configuration related to cell’s functional capacity. However, whether and how different ER subdomains play a role in optimizing the functional capacity of the cell in response to metabolic demand is unclear. Moreover, the upstream signals that regulate ER shape dynamics are not known. In this proposal, we aim to use state-of-the-art metabolic flux approaches to investigate how the structural regulation of ER controls lipid and glucose fluxes in cells. Additionally, by using enhanced Focused Ion Beam Scanning Electron microscopy and super-resolution fluorescent microscopy, we will interrogate the ER’s architectural response to nutrient sensing and signaling pathways. Lastly, we will perform CRISPR-Cas9 screens, coupled with high-content imaging and deep learning-based analysis to discover novel regulators of ER shape and function. This work will provide novel insight into how organelle shape and dynamics regulate cellular function and health. It will introduce a new perspective to the field by incorporating subcellular architectural remodeling as a new layer of metabolic regulation.