Award details

Unveiling the molecular mechanisms to modulate peroxisome dynamics and abundance for improvement of cell performance

Reference	BB/R016844/1
Principal Investigator / Supervisor	Professor Michael Schrader
Co-Investigators / Co-Supervisors	Dr Peter Petrov, Dr David Richards, Professor Charles Winlove
Institution	University of Exeter
Department	Biosciences
Funding type	Research
Value (£)	481,678
Status	Completed
Type	Research Grant
Start date	01/12/2018
End date	30/09/2022
Duration	46 months

Abstract

In this project we will address fundamental open questions related to the molecular mechanisms and pathways that mediate and regulate organelle dynamics and abundance. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions. Peroxisomes have vital, protective roles in lipid metabolism, signalling, and the combat of oxidative stress, thus influencing developmental and ageing processes. We will now apply novel tools and cellular models to assess and modulate organelle dynamics and abundance, which may improve cell performance in health and disease. In this project we will (1) combine molecular cell biology, biochemical and microscopic approaches to determine the molecular mechanisms modulating peroxisome membrane dynamics and abundance in humans. We will (2) apply biophysical approaches to investigate membrane remodelling and lipid interaction of key proteins. Furthermore, we will (3) combine screening approaches with physiological studies to identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) apply mathematical and computational modelling to develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions. This interdisciplinary project applies molecular cell biology, biophysical, biochemical and screening approaches, mathematic modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. It will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders.

Summary

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. To adapt to the changing physiological requirements of a cell or organism, organelles have to constantly adjust their number, shape, position, and metabolic functions accordingly. This requires dynamic processes which modulate organelle abundance by organelle formation (biogenesis), degradation (autophagy), or inheritance (cell division). Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently. Our work has revealed that peroxisomes are extremely dynamic and can form from pre-existing organelles in a multistep process which requires remodelling of the peroxisomal membrane, the formation of tubular membrane extensions which subsequently constrict and divide into several new peroxisomes. Defects in peroxisome dynamics and multiplication have been linked to age related disorders involving neurodegeneration, loss of sight and deafness. Despite their fundamental importance to cell physiology, the mechanisms that mediate and regulate peroxisome membrane dynamics and abundance in humans are poorly understood and a biophysical model is missing. Understanding these mechanisms is not only important for comprehending fundamental physiological processes but also for understanding pathogenic processes in disease etiology. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions. In this research project, we will (1) assess the role of key proteins in peroxisome division to unveil the molecular mechanisms modulating peroxisome abundance, (2) apply biophysical approaches to investigate protein-lipid interaction and membrane remodelling, (3) identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions. In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with biophysical and mathematical approaches as well as novel tools and models in human cell biology. We will apply molecular cell biology, biophysical, biochemical and screening approaches, mathematical modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. Specifically, this research project will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders. We will generate new tools and models for assessing and modulating organelle dynamics, which may help to improve cell performance. Understanding how to modulate organelle dynamics and abundance and to use the protective functions of organelles will be of significant biological and medical importance. It may contribute to the development of new therapeutic approaches in healthy ageing and age-related disorders.

Impact Summary

This project seeks to deliver ongoing national and international i) academic, ii) medical, iii) political, iv) economic and v) social impact from multi-disciplinary research by building knowledge around the link between organelle dynamics/abundance, cell performance and dysregulation which may result in disease (i, ii, iii, iv), and by improving understanding of associated proteins, their impact on healthy ageing, age-related disorders and diagnostics (i, ii, iv, v). By focusing on the topic of organelle dynamics and regulation of organelle abundance, its findings are highly relevant given the current importance of cellular redox balance and lipid/energy regulation in maintaining normal cellular homeostasis and in the ageing process. In the longer term, this new knowledge will also help inform on risk factors 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 dynamics and multiplication impact on normal and disease processes; it is therefore envisaged that this work will be beneficial for academics and clinicians as well as health professionals, charitable bodies 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 cell physiology which have the potential to impact upon developments within both the biological and medical research communities and could enable the identification of new drugs and approaches to modulate organelle dynamics, which may help to improve cell performance in health and disease. 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 multipledisciplines 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 dynamics and regulation of abundance 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 and modulating organelle dynamics to improve cell performance 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. Through cooperation with industry (Novatis, CH) this research has potential impact on the identification of drugs and the development of novel therapeutic approaches for healthy ageing and treatment of age-related disorders (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 the University of Exeter's (UoE) Innovation, Impact and Business Team (UoE IIB) have established networks of industry contacts, and research findings will be formally reviewed annually, to explore and coordinate links with business and key project partners. The UoE 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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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