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

ec2bed07-9430-4938-8025-d897bb5261a8

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BBSRC
BBSRC
BBSRC
BBSRC
BBSRC

£2,113,530

Sept. 30, 2016

Dec. 3, 2019

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.

Technical Abstract:
In this project we will address fundamental open questions related to the molecular mechanisms and pathways that mediate and regulate inter-organelle cooperation and lipid metabolism between peroxisomes (PO) and the endoplasmic reticulum (ER). Our overall aim of this project is to acquire novel insights into PO-ER association, lipid metabolism and transfer processes in normal and disease conditions. PO play an important cooperative role in the metabolism of cellular lipids and cellular energy regulation thus influencing developmental and ageing processes. We will now apply novel tools and cellular models to assess how novel peroxisomal lipid-binding proteins contribute to organelle communication, the regulation of lipid metabolism and the development of organellopathies.
In this project we will (1) combine biochemical and ultrastructural approaches to determine the molecular mechanism underlying PO-ER association and identify and characterise specific proteins involved in this interaction to understand the PO-ER relationship and its impact on disease pathology. We will (2) develop fluorescence-based approaches to investigate the function of these proteins in PO membrane dynamics and (3) in the specific degradation of PO; both processes have an impact on human development and healthy ageing. Furthermore, we will (3) assess the role of novel peroxisomal lipid-binding proteins in fatty acid transport and PO fatty acid beta-oxidation to understand the pathophysiology of a novel PO-related disorder. This interdisciplinary project applies molecular cell biology, biochemical approaches, proteomics and cutting edge imaging techniques to elucidate the link between organelle interplay, lipid metabolism and disease pathology. It will improve our understanding of novel lipid-binding proteins and their impact on healthy ageing and common, degenerative disorders.

Potential Impact:
The research is considered to have ongoing national and international i) academic, ii) medical, iii) political, iv) economic and v) social impact by building knowledge about the link between organelle communication, the regulation of lipid metabolism and the development of organellopathies and common, degenerative diseases (i, ii, iii, iv) and improving our understanding of novel lipid-binding proteins and their impact on healthy ageing and age-related disorders (i, ii, iv, v). By focusing on the topic of organelle interplay and lipid homeostasis, its findings are highly relevant given the current importance of altered cellular energy regulation as a risk factor for the initiation and progression of common, age-related diseases such as obesity, diabetes, cardiovascular disease, neurodegeneration and cancer. The research proposed is novel and highly important to aid our understanding of how organelle interplay contributes to metabolic signalling pathways and lipid metabolism that impact on disease processes; it is therefore envisaged that this work will be beneficial for academics and clinicians as well as health professionals, charity and others engaged with health promotion by enhancing quality of life, health, wellbeing and healthy ageing. The work aims to understand fundamental processes in human cell biology, organelle biogenesis and lipid homeostasis which have the potential to impact upon developments within both the biological and medical research communities and could enable the identification of new targets to modulate and improve the regulation of lipid metabolism and cellular energy regulation. This in turn has the potential to benefit understanding of healthy ageing, degenerative and other age-related diseases with the potential to be exploited in both the pharmacological and public health sectors. The fusion of distinct disciplines that constitutes this work will help to highlight to the general community the potential benefits of systems-led and inter- and multi-disciplinary research that UKRC are championing. The reason for this potential is that the mechanisms of organelle interplay and regulation of lipid homeostasis are poorly understood, but are essential for cellular viability and development of the organism. An additional outcome of this research will be the development of new tools and models for assessing organelle interplay and the role of lipid-binding proteins in health and disease, which will be of benefit to the scientific community as a whole and impact on the development of both biological and medical science in this field.
Knowledge gained from this study promises to help the identification of novel targets for drug development (of benefit to the UK and European pharmaceutical and health sectors) as well as in the diagnosis of pathophysiological conditions and disorders (public health sector). The project team and University Research and Knowledge Transfer Office (RKT) have established networks of industry contacts, and research findings will be formally reviewed annually, to assess the potential for specific engagement with potential industrial partners. The University of Exeter has excellent links with the wider public with regular events with contributions from research staff. Researchers make regular school visits to explain their research and run events as part of National Science week. Programmes such as this and other outreach activities are critical for the long-term maintenance of the UK science base. This is also aided by the transfer of knowledge and skills between academia and industry. The PDRA and Technician will both receive full and relevant training. Several former PhD students are now working within the biotechnology or biomedical sector.