The role of hepatic Endoplasmic Reticulum architecture in metabolic homeostasis and disease

Summary

This research project aims to investigate how alterations in hepatic endoplasmic reticulum (ER) architecture, particularly involving the protein RRBP1, contribute to metabolic dysfunction and the development of Metabolic dysfunction Associated Fatty Liver Disease (MAFLD).

What they want

The project will explore the mechanisms by which RRBP1-driven rough ER sheet-mitochondria interaction regulates hepatocyte adaptation to nutritional challenges like fasting, and how its dysregulation in obesity leads to metabolic dysfunction. Specific aims include characterizing the impact of liver-specific RRBP1 manipulation on liver metabolism in mice, unraveling how ER-mitochondria proximity regulates organelle function, and determining the role of ER architectural remodeling in diet-induced fatty liver disease in both mice and humans. The research will also test if targeting ER structure via RRBP1 overexpression can mitigate metabolic stress in MAFLD.

Deliverables

Characterization of the impact of liver-specific RRBP1 loss and gain of function on liver metabolism in mice
Testing of the hypothesis that rough ER-mitochondria proximity allows mitochondria to adapt to fasting
Determination of the impact of diet-induced fatty liver disease on ER structural remodeling in mice and humans using FIB-SEM imaging and machine learning-based organelle segmentation
Testing if targeting ER structure by overexpression of RRBP1 can improve metabolic stress in MAFLD

Technical requirements

FIB-SEM imaging
Machine learning-based organelle segmentation