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Proteins carry out the chemical reactions necessary for life, and are used as building blocks to assemble key components of cells, giving them shape and structural integrity. During a cell's life cycle, different proteins are produced as needed and then recycled when they have finished their work. To perform their jobs, proteins may themselves undergo chemical modifications, interact with other proteins and adopt a variety of different shapes. Our understanding of protein shape, structure and function has been enormously useful in furthering our molecular understanding of life, leading to successful drug-discovery efforts, methods to improve crop production and other applications with economic and societal benefits. While most proteins adopt a regular 3D shape, it is now accepted that large sections of many proteins termed intrinsically disordered regions (IDRs) have no fixed shape. These "shape-shifting" properties allow the proteins that contain them to perform different jobs at different times and in different parts of the cell by dynamically adopting different shapes in response to their environment. To truly understand the "molecular rules of life", it is therefore necessary to understand how the structures of these "shape-shifters" changes with time, how this influences what other proteins they interact with, how this impacts on the healthy/unhealthy cells life-cycle and ultimately how to control these properties using chemistry. In this research we will study a protein that plays an essential role in the cells life-cycle (Aurora-A) e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts that have not yet been successful. Aurora-A fulfils different jobs at different times and in different parts of the cell by interacting with multiple different "shape-shifting" proteins. We will use an integrated and state-of-the-art chemical and biological approach to characterise when, where and which interactions between shape-shifting proteins and Aurora-A define its biological function. In doing so, we will identify methods to switch off the interactions between Aurora-A and specific shape-shifters, which can be used to further understand the functional role of these proteins and provide starting points for drug discovery. About a third of human proteins are thought to have an intrinsically disordered region, and our study will help biologists to investigate the properties and roles of these poorly-understood proteins. In the longer term, the ability to manipulate "shape-shifting" proteins will open up a new route to developing medicines to treat a wide range of diseases.

The human genome project and the technological advances that accompanied it, including the recent advent of the "thousand dollar genome" have opened up new possibilities in medicine, including the opportunities for more precise, molecular diagnoses and personalised treatment based on genome information. The technologies are now at a stage where, with appropriate validation and optimisation, they will soon be moved into routine clinical care to accelerate disease diagnosis and improve patient outcomes. However, to introduce this "step-change" in diagnostics and pathology successfully into the clinic, will require the coordinated action of expertise from multiple fields, including the physical sciences, and training of modern-style pathologists to be familiar with multiple advanced technologies. The Edinburgh-St Andrews Molecular Pathology Node will integrate the proven strengths of the Universities of Edinburgh and St Andrews in molecular pathology and diagnostics (training, development and clinical implementation), image analysis of complex phenotypes and computing, with the breadth of genome medicine and genome sciences experience available within the Universities and NHS Lothian. These strengths include institutes and centres with substantial existing MRC, EPSRC and charitable investment including the MRC Human Genetics Unit, MRC Farr Institute, CRUK Cancer Centre and EPSRC-funded supercomputer and optical imaging facilities. The main aims of the Node will be: (1) training a new generation of molecular pathologists capable of handling modern genome-analysis-aided approaches to diagnosis and treatment of human disease; (2) developing new tests and clinical applications utilizing the advantages of novel technologies; (3) creation of new algorithms, standard operating procedures, data flow schemes and advanced statistical and computational methods that will directly facilitate analysis of the vast and complex data generated by genomics and imaging methods, to implement these new molecular pathology approaches in the clinic. We will focus on areas of clinical need where we believe genome-based assays will most rapidly enter the clinic, particularly the genetic diagnosis of acutely ill children and babies, genetic diagnosis in fetuses with congenital malformations, inherited subtypes of common diseases in adults, and the diagnosis and monitoring of patients with cancer through development of "liquid biopsies" from cell-free DNA in circulating blood. A significant part of the proposed work will be done by practicing clinicians and diagnosticians in the framework of a purpose-designed Masters Research Programme in Molecular Pathology, to which experts in many fields will contribute, including those in the UK National External Quality Assurance Scheme (UK NEQAS) for Molecular Genetics and Pathology, which is based at the Royal Infirmary in Edinburgh. Together with our world-leading partners from the biotechnology and pharmaceutical industry, we will develop and integrate these genome and imaging-based methods to implement new diagnostic methods in healthcare and to produce and sustain a generation of "genomically-skilled" pathologists who will be leaders in the introduction of these methods into routine practice for the next generation of doctors and scientists.

Collectively, fungal diseases pose a greater threat to animals, plants and ecosystems than other types of infectious micro-organism. Fungal infections of man kill millions and most often occur in patients with severe underlying health conditions such as cancer, or chronic lung disorders such as cystic fibrosis. Fungal infections of plants destroy enough crops annually to feed many millions of people. However, there are a very limited number of antifungal drugs available for use agriculturally or in the clinic and some classes of antifungal drugs, for example the azoles. are therefore used to treat both human and plant fungal infections. In 2018 azole-based fungicides accounted for 34% of the antifungal agents used to treat crops. Worryingly, resistance to all classes of available antifungal drugs is increasing and azole resistance occurring in agricultural settings crosses over into the clinic in around 40% of cases in some settings. This project builds on decades of previous genetic and infection studies, including a PhD project where a new set of chemicals were showed as having antifungal activity. These chemicals attack a fungal signalling mechanism needed for infection and invasion by fungal pathogens in man, plants, animals and we will now work to understand how they work. We will also try to make them more potent, and work with industry to develop them for use in agriculture or in the clinic.

Proteins carry out the chemical reactions necessary for life, and are used as building blocks to assemble key components of cells, giving them shape and structural integrity. During a cell's life cycle, different proteins are produced as needed and then recycled when they have finished their work. To perform their jobs, proteins may themselves undergo chemical modifications, interact with other proteins and adopt a variety of different shapes. Our understanding of protein shape, structure and function has been enormously useful in furthering our molecular understanding of life, leading to successful drug-discovery efforts, methods to improve crop production and other applications with economic and societal benefits. While most proteins adopt a regular 3D shape, it is now accepted that large sections of many proteins termed intrinsically disordered regions (IDRs) have no fixed shape. These "shape-shifting" properties allow the proteins that contain them to perform different jobs at different times and in different parts of the cell by dynamically adopting different shapes in response to their environment. To truly understand the "molecular rules of life", it is therefore necessary to understand how the structures of these "shape-shifters" changes with time, how this influences what other proteins they interact with, how this impacts on the healthy/unhealthy cells life-cycle and ultimately how to control these properties using chemistry. In this research we will study a protein that plays an essential role in the cells life-cycle (Aurora-A) e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts that have not yet been successful. Aurora-A fulfils different jobs at different times and in different parts of the cell by interacting with multiple different "shape-shifting" proteins. We will use an integrated and state-of-the-art chemical and biological approach to characterise when, where and which interactions between shape-shifting proteins and Aurora-A define its biological function. In doing so, we will identify methods to switch off the interactions between Aurora-A and specific shape-shifters, which can be used to further understand the functional role of these proteins and provide starting points for drug discovery. About a third of human proteins are thought to have an intrinsically disordered region, and our study will help biologists to investigate the properties and roles of these poorly-understood proteins. In the longer term, the ability to manipulate "shape-shifting" proteins will open up a new route to developing medicines to treat a wide range of diseases.