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\n \n Damian Tyler - Cardiac Sciences / Metabolism & Endocrinology - 'Assessment of Cardiac Metabolism Using Hyperpolarized Magnetic Resonance Imaging'\n \n \n

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The role of abnormal cardiac substrate metabolism in the development of many cardiovascular diseases and the therapeutic potential of interventions targeting cardiac substrate metabolism are unclear. Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) have long been used to monitor cardiac structure and function. However, the application of MRI/MRS for metabolic imaging has been limited by an intrinsically low sensitivity. Hyperpolarized Magnetic Resonance (hp-MR) is a new technique that yields greater than 10,000-fold signal increases in MR images and enables unprecedented real-time visualization of the biochemical mechanisms of abnormal metabolism. This allows measurement of instantaneous rates of substrate uptake and enzymatic transformation in vivo, providing a sensitive assessment of disease and a new means to monitor treatment response. This project will explore the application of hp-MR in the study of cardiovascular disease, enabling the assessment of pyruvate metabolism through the key metabolic enzyme, pyruvate dehydrogenase, and how it can be modulated as a therapeutic target.

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\n \n Richard Wade-Martins - Neuroscience - 'Human stem cell models of neurological disease'\n \n \n

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We seek highly motivated DPhil students with either a scientific or medical background to join our laboratory to work on the molecular mechanisms of neurological and neurodegenerative diseases. Techniques in molecular genetics have allowed the identification of genes and proteins with an important function in both familial and sporadic forms of Parkinson\u2019s disease and Alzheimer\u2019s disease. Our laboratory focusses on following up these genes and proteins to better understand disease mechanisms to identify potential therapeutic targets for further translational studies. To undertake this, we work with induced pluripotent stem cells (iPSCs) generated from patients with Parkinson\u2019s, Alzheimer\u2019s and related disorders. iPSC-derived patient models promise to revolutionize the study of neurodegenerative diseases in which the critical cell type has been previously inaccessible. The capability to generate, engineer, differentiate and phenotype iPSC-derived neurons and glia from patients with neurodegeneration allows for the study of highly physiological human models of disease. We have undertaken a detailed phenotypic analysis of patient and control iPSC-derived neurons and glia and identified and published strong cellular phenotypes using robust assays suitable for studying disease mechanisms across a range of new projects.

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\n \n Clive Wilson - Development & Cell Biology - 'Dissecting the conserved in vivo regulation of Rab11-exosomes in Drosophila'\n \n \n

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Exosomes are nano-sized vesicles secreted from the endosomal compartments of cells. They carry a multitude of different bioactive cargos, including proteins, RNAs and lipids that can reprogramme target cells. Exosomes have been implicated in many pathologies, in particular cancer, where they can prime pre-metastatic sites, induce drug resistance and suppress the immune system. However, they are also involved in complex physiological cell-cell signalling events. For example, we found that exosomes secreted into seminal fluid in the male accessory gland of the fruit fly reprogramme female behaviour, so she rejects other males that try to mate with her. Using this fly model in which exosomes are made inside unusually large intracellular compartments that can be imaged in real-time, we identified a novel evolutionarily conserved exosome subtype, called Rab11-exosomes, which is the primary mediator of key physiological and cancer-relevant exosome functions, despite representing a small fraction of all secreted vesicles. We recently identified multiple new conserved regulators of Rab11-exosomes by combining human Rab11-exosome proteomics with fly genetic analysis. This project will involve analysing these regulators further, focusing on how they shape Rab11-exosomes, coat these exosomes with extravesicular proteins and traffic them to the cell surface, mechanisms that are all potential targets for future exosome subtype-specific therapies. See https://www.biorxiv.org/content/10.1101/2024.03.28.586966v2 for recent developments.

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\n \n Clive Wilson - Metabolism & Endocrinology - 'Regulation of microcarriers: new messengers of cell-cell and reproductive signalling in higher organisms'\n \n \n

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Cell-cell communication controls almost all physiological processes in multicellular organisms and is defective in many diseases. Our group has developed the male reproductive accessory gland in the fruit fly Drosophila melanogaster as a new genetic model to study the fundamental processes involved in secretion and signalling. Employing this system, we discovered that multiple secreted signals, including Sex Peptide, the central regulator of female post-mating responses, are packaged into lipophilic structures that we call microcarriers, which stabilise these proteins in the gland and then permit their rapid release when deposited in the female uterus. We have now found that evolutionarily conserved derivatives of the lipid ceramide and the enzymes that produce them have multiple roles in generating microcarriers. In humans, components of this microcarrier biogenesis pathway are required for several biological processes in humans. They are highly upregulated in cancer and implicated in metabolic disease and obesity. In this project, additional new evolutionarily conserved regulators of microcarriers that we have recently identified will be characterised using advanced genetic and imaging technologies to determine their functions. We anticipate that this work could provide the stepping stone to extend our studies into human cells and assess the relevance of microcarriers to human health and disease.

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\n \n Clive Wilson - Neuroscience - 'Regulation of physiological and pathological amyloidogenesis in Alzheimer\u2019s disease and beyond'\n \n \n

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Amyloidogenesis, the aggregation of soluble proteins into insoluble fibrils, has multiple biological functions in health and disease, eg, in Alzheimer\u2019s Disease (AD), aggregations of A-beta peptides, cleaved products of Amyloid Precursor Protein (APP), form plaques, while peptide hormones naturally condense into insoluble, dense-core granules (DCGs), stored within secretory vesicles until release. However, in vivo assays to analyse how amyloidogenesis is initiated are lacking. We have developed a new cellular model for DCG biogenesis, the Drosophila prostate-like secondary cell (SC). These cells have highly enlarged (5 micron diameter) DCG compartments, permitting the rapid process of DCG assembly to be followed by light and fluorescence microscopy in real-time. We find DCG formation requires the fly homologues of APP, called APPL, and another amyloidogenic protein, TGF-beta-induced, as well as intraluminal vesicles that are secreted as so-called Rab11-exosomes. Genetic dissection of the DCG biogenesis process in SCs shows that it is disrupted by mutant proteins linked to AD, including A-beta peptides and Tau, producing several AD-like phenotypes, and strongly suggests that these previously unappreciated defects are key triggers in pathology. This project will characterise this process further in flies and investigate how pathological defects can be suppressed by genetic manipulations, drugs and dietary changes. See https://www.biorxiv.org/content/10.1101/2024.03.28.586966v2 for recent developments.

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\n \n Manuela Zaccolo - Cardiac Sciences - 'Nanodomain signalling in the heart'\n \n \n

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cAMP and its effector PKA are key regulators of cardiac function and defective cAMP/PKA signalling is a hallmark of heart failure (HF) and genetic cardiomyopathies. This signalling pathway is also at the core of current therapies, which however remain unsatisfactory and need improvement. Current therapeutic strategies largely ignore signalling processes occurring in cardiomyocytes at the subcellular level. We use FRET-based imaging approaches to measure cAMP/PKA signalling in real-time and with high spatio-temporal resolution. Using this approach we were able to directly show that cAMP/PKA signalling is highly compartmentalised within subcellular nanodomains (1, 2), with different sites affecting different functions (2). In a recent study we found that adrenergic stimulation generates pools of cAMP with different amplitude and kinetics at the plasmalemma and at the myofilaments and that such local regulation is disrupted in HF (2). Local PKA activity is dictated by local [cAMP], controlled at each specific site by particular adenylyl cyclases (AC) and phosphodiesterases (PDE) isoforms. Local phosphorylation of targets results from the balance of local PKA and phosphatase (PP) activity. All these components can potentially be manipulated to affect local signalling. Compartmentalization of signalling provides a unique opportunity to intervene therapeutically with increased precision by selectively targeting individual nanodomains to affect only the desired function. Recently, we have conducted an integrated PDE phospho-interactome ananlysis that unveiled multiple novel and non-obvious cAMP nanodomain under specific regulation of PDE isoforms (4). We are currently validating these data and characterising the function reglated by these novel nanodomans.The overall aim of our work is to build a detailed map of cAMP nanodomains in cardiac myocytes . The map will be used as a blueprint to assess alterations in pathological conditions to gain novel mechanistic understanding of pathological processes at the molecular level. This information will guide development of new strategies for targeted therapeutic interventions.The project will test novel FRET-based reporters targeted to specific subcellular sites in cardiac myocytes to establish local cAMP dynamics at key signalling nodes that participate in the regulation of cardiac myocyte function. The work will involve biochemical and genetic approaches to study cAMP signalling at these sites in animal models of HF and in human cardiac myocytes differentiated from inducible pluripotent stem cells.

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\n \n Pawel Swietach - Cardiovascular, Cell physiology Metabolism & \"Urine-on-a-Strip: Point-of-Care Detection of Intravascular Haemolysis\"\n \n \n

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**Fully funded project** Clinical feasibility study and refinement of a rapid, point-of-care urinary test for detecting intravascular haemolysis

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Visit this page for our entry criteria and what you need to make an application, alongside some further resources to support you.

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