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One of the most devastating burdens to human health is spinal cord injury, which occurs primarily through car or sport accidents and it wrecks peoples? lives with paralysis than can affect all four limbs. The medical challenge is to promote the regeneration of the spinal cord, to allow functional recovery. The efforts to promote regeneration have been partly hampered by the fact that upon injury the cellular environment becomes inhibitory to axonal growth. One challenge is thus to turn the cellular environment into one that will promote axonal growth. However, this requires knowledge of how axons interact with glia during growth, how to eliminate secondary death of neurons and glia and how to promote the re-establishment of myelinated, functional neural networks. Unfortunately, little is still understood of the underlying molecular mechanisms that while keeping neurons and glia alive contribute to the restoration of functional axonal connections. Similarly, in neurodegenerative diseases (i.e. Multiple Sclerosis, Parkinson?s disease, Alzheimer?s), neurons and glia die and the promotion of neuronal and glial survival is a strategy to alleviate these diseases. However, it is unknown how to implement the restoration of normal neuronal connections and function from cells that are maintained alive. For the last five years, I have been studying how neuron-glia interactions link the promotion of neuronal and glial survival with the formation of axonal trajectories. I study these processes during development of the nervous system, as this knowledge is absolutely essential to work out how they can be implemented or manipulated upon injury or disease. I use the Drosophila equivalent of the spinal cord as a model system because it is possible to study and manipulate individual neurons and glia with single cell resolution, and in vivo, something not yet possible in vertebrate models. Furthermore, working with Drosophila is very cheap, progress is fast because the fly life cycle is short and experimentation with flies does not raise ethical concerns. Findings in Drosophila are totally relevant to the understanding of the human spinal cord and brain. Drosophila has long been one of the most powerful genetical model organisms to work out molecular pathways underlying universal cellular functions. Many important molecules involved in the development of the human brain and disrupted in human cancers were discovered in Drosophila. The fruit-fly is also a powerful model organism to model neurodegeneration and neurotrophic interactions are known to occur in flies. With this proposal, I aim to gain from Drosophila information of how a homologue of a trophic factor already known to exist in humans functions in axon guidance and targeting during development. Using the power of Drosophila genetics and of the sequenced genomes, I also aim to discover novel trophic factors that maintain neurons alive, which I anticipate ultimately will be relevant for humans too.

The PicoPix project will develop and deliver pixelated and radiation hard Low Gain Avalanche Detectors (LGAD) with sub 30-ps timing resolution for 4D particle tracking in high energy physics and imaging applications. Starting from AC-coupled LGADs, developed in the context of the RD50 collaboration, PicoPix will use novel techniques to redefine the state-of-the-art in LGAD fabrication: a) pixelation, with typical dimension in the order of few tens of μm; b) timing resolution, through thinner detectors; and c) radiation-hardness, through novel designs of the active detection volume. PicoPix will push the boundaries in many fields from fundamental science to industrial applications. The fellow, Dr Reynolds, an expert in hadron collider physics with broad experience in simulations, analysis techniques, and data interpretation, has experience in characterisation of silicon detectors. The supervisors, Dr Tricoli and Prof Nikolopoulos, have significant experience and leadership in detector instrumentation and physics analysis. The former leads the Brookhaven National Laboratory (BNL) Fast-Timing Silicon Sensor Test- ing Laboratory, and the latter played a key-role in the commissioning of the Irradiation Facility at the University of Birmingham (UoB). The hosts, UoB and BNL, have excellent facilities enabling PicoPix, including the BNL Silicon Fabrication Facility and the Birmingham Instrumentation Laboratory for Particle Physics and Applications (BILPA). The secondments and visits, including at Fermilab, DESY, and CERN, and collaboration with other academic fields and industries ensure PicoPix’s success and a unique environment for Dr Reynolds’ development.

Background: The development of safe and effective therapies to treat fibrosis is a major priority for patients with glaucoma. This ocular disease is characterised by elevated intraocular eye pressure (IOP), resulting from ineffective drainage of the aqueous humour. This in part is caused by the blockage of the aqueous humour outflow due to increased extracellular matrix deposition in the trabecular meshwork (TM)1. Over time the increased pressure can damage structures in the eye resulting in vision loss. Current therapeutic strategies to lower the IOP include indefinite eye-drops, which can cause side effects, or complex filtration surgery. Fibrosis at the time of surgery is reduced by treatment of tissue with anti-metabolites such as mitomycin C at the time of surgery, but this is associated with local toxicity predisposing to leaks, tissue breakdown and infections2. The lack of safe and effective anti-fibrotic treatments presents an important clinical challenge. It is therefore important to identify novel targets for drug development. Scarring and fibrosis of the eye in glaucoma is associated with marked structural and functional reorganisation of the trabecular meshwork, the main site of resistance to fluid outflow in the eye. The pathophysiology of glaucoma, has not yet been fully elucidated and investigators are mainly reliant on in vivo rodent models3. This in part has been due to the lack of meaningful tissue engineered and suitable ex vivo models. In order to identify novel targets and develop new treatments, we have been collaborating with Birmingham and Midlands Eye Centre to successfully collect TM tissue from patients with and without glaucoma. Therefore, this human data source will not only provide us with novel insights into the underlying mechanisms of the disease but also provide us with new pathways to target as a therapeutic strategy. Aims: Our aim is design a novel in vitro 'organ on a chip' model to understand the pathology which occurs in the TM in glaucoma and to identify novel anti-scarring compounds for the treatment of glaucoma. We will achieve this by investigating the mechanisms that control fibrosis in human trabecular meshwork (TM) and the interaction with Schlemm's Canal cells. We will develop co-culture systems in 3D models4 which mimic the human trabecular meshwork/Schlemm's canal and then use this model for testing and screening new anti-scarring treatments. In addition, we will develop dynamic perfusion models within ex vivo assays derived from explant human tissues (Ethics and sourced material in place) to investigate the pressure inducing effects of scarring in the eye. Using aligned optical coherence tomography (OCT) to the 'chip' models we will also define changes in mechanical properties of the engineered human TM alongside cell and molecular outcomes of treatments. Training outcomes: The PhD Candidate will be supervised by an ocular biologist (Dr Hill), a biomaterial scientist (Prof Grover) and tissue engineer (Prof A El Haj) and will have close input from a clinical ophthalmologist (Mr Masood, Glaucoma Consultant) and industrial support from the Cell Guidance Systems Ltd (Dr Michael Jones). The overall aim is to reduce the need to use our rodent glaucoma models to assess new anti-scarring treatments. Within this project the student will expect to receive training on human tissue processing (samples derived from patients), cell culture techniques for developing 3D in vitro models reconstructing collagen and elastin scaffolds (to model the TM) and to develop skills in setting up ex vivo porcine and human models for understanding glaucoma pathology and to assess candidate treatments. Students would learn routine molecular biology techniques (immunocytochemistry, western blots, PCR) in order to characterize the models and assess effects of anti-scarring treatments and have the opportunity for both industrial and international placements.

Cardiovascular disease is the leading cause of death world-wide, affecting both men and women. Myocardial infarction and ischemic stroke are two severe consequences of cardiovascular disease caused by formation of an occlusive thrombus. Blood coagulation and thrombus formation is a complex interplay between clotting factors, platelets and endothelial cells lining the blood vessels that often involve interactions with leukocytes and other inflammatory cells. I propose to study a novel receptor on platelets, PEAR1, and its role in haemostasis, inflammation and thrombosis. I will use unique, synthetic poly-sulfated sugars that I have characterised as novel agents to activate PEAR1 and take advantage of the 30 years of experience of my host, Professor Watson, in studying platelet activation, and the recent identification (unpublished) of the natural ligand in the body which activates PEAR1. I will use state-of-the-art methodology available in Birmingham including flow chamber studies, CRISPR-CAS knock-down, phosphoproteomics, super-resolution and light sheet microscopy, intravital microscopy and a PEAR1 deficient mouse model to test my hypotheses that PEAR1 plays a critical role in thrombus stabilisation at sites of injury and drives thrombo-inflammatory disease in the vasculature. Uncovering the role of the novel receptor PEAR1 may lead to new treatment strategies to combat thrombosis.