Unveiling novel functions of peroxisomal lipid-binding proteins in interorganellar cooperation and regulation of lipid metabolism

点击翻译按钮获取中文摘要

One of the hallmarks of eukaryotic cells is the presence of membrane-bound compartments (organelles), which create different optimised environments to promote various metabolic reactions required to sustain life. For the entire cell to function as a unit, coordination and cooperation between specialized organelles must take place. Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Peroxisome dysfunctions contribute to several inherited organelle disorders with diverse pathology which are often difficult to diagnose and to treat. Peroxisomes play pivotal cooperative roles in the metabolism of cellular lipids and reactive oxygen species (ROS) and influence neuronal development and ageing processes. Lipids have many important functions in the cell and organism, for example as energy source, signalling molecules or components of cellular membranes. The disturbance of cellular lipid balance and altered cellular energy regulation is a risk factor for the initiation and progression of common, age-related diseases such as diabetes, cardiovascular disease, neurodegeneration, cancer and obesity. Peroxisome dysfunctions have been linked to degenerative disorders. Moreover, important roles for peroxisomes in signalling and the fine-tuning of cellular processes are emerging, which integrate them in a complex network of interacting cellular compartments. Despite this importance for human health and disease, our knowledge on how peroxisomes interact and communicate with other organelles and contribute to the regulation of cellular lipid homeostasis that impact on normal physiology and disease processes is scarce. The overall aim of this project is to acquire novel insights into peroxisome-organelle association, lipid metabolism and transfer processes in normal and disease conditions.In this project we will (1) reveal the molecular mechanism underlying peroxisome-organelle association and identify and characterise specific proteins involved in this interaction to understand the organelle interplay and its impact on disease pathology; we will (2) develop approaches to investigate the function of these proteins in peroxisomal membrane dynamics and (3) in the specific degradation of peroxisomes; both processes have an impact on human development and healthy ageing. Finally, we will (4) assess the role of novel peroxisomal membrane proteins in the transport and degradation of fatty acids to understand the pathophysiology of a novel peroxisome-related disorder. In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with novel tools and models in human cell biology. We will apply molecular cell biology, biochemical approaches, proteomics and cutting edge imaging techniques to elucidate how novel peroxisomal membrane proteins contribute to organelle communication, the regulation of lipid metabolism and the development of organelle-based disorders. Specifically, this research project will improve our understanding of novel lipid-binding proteins and their impact on healthy ageing and common, degenerative disorders. We will generate new tools and cellular models for assessing organelle interplay and the role of novel membrane proteins in health and disease. Understanding of the link between organelle interplay, lipid metabolism and disease pathology will be of significant biological and medical importance. It may contribute to the discovery of new targets to modulate the regulation of lipid metabolism and cellular energy regulation in healthy ageing and age-related disorders.