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Results

Regulation and function of PINK1 kinase in Parkinson's disease 10 Apr 2018

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) cause familial Parkinson's disease. My laboratory has contributed mechanistic understanding into how PINK1 functions in a common signalling pathway with the ubiquitin E3 ligase Parkin to regulate mitochondrial quality control. Highlights of our past work include the unexpected discovery that PINK1 can phosphorylate ubiquitin and the recent crystal structure of insect PINK1. To date it remains unknown whether our current understanding of PINK1 biology is conserved in neuronal cell types and tissues of physiological relevance to Parkinson's. To address this, we will employ quantitative proteomics to uncover novel substrates of Parkin in primary mouse neuronal systems as well as tissues of a Parkin Ser65Ala knock-in mouse model, we have characterised, that exhibits mitochondrial dysfunction in vivo. We will investigate how mutations in other Parkinson's genes particularly VPS35 regulate PINK1 signalling. We will investigate the mechanism by which human PINK1 becomes activated including solving the crystal structure of full length human PINK1 bound to its substrate ubiquitin. These analyses will provide a framework of knowledge that will be critical for the development and evaluation of PINK1 activators that are currently being explored as a potential therapy against Parkinson's.

Amount: £2,088,664
Funder: The Wellcome Trust
Recipient: University of Dundee

Expanding the druggable proteome of immune cells - towards synthetic immune regulation 24 Apr 2018

Drugs capable of manipulating the innate immune system have the potential to treat a broad spectrum of human diseases. However, to realise this potential, we need both a better understanding of the biological processes that regulate innate immunity and to radically expand the scope of potentially druggable protein targets. My research will address both these limitations. I will use activity-based protein profiling to identify proteome-wide sites of ligandability in primary human immune cells and drive the development of frontier chemical probes, which can be used to dissect the principles of immune regulation or provide leads for drug development. In particular, my research will focus on proteins involved in non-degradative ubiquitylation, a critical pathway mediating signal transduction in innate immunity. My specific aims are to: Map the interactions of small molecules with proteins in primary human innate immune cells on a proteome-wide scale. Develop targeted mass spectrometry and synthetic biology platforms to efficiently verify, establish structure-activity relationships and explore the functional consequences of small molecule-protein interactions. Develop high-quality chemical probes for proteins that play critical roles in innate immunity. This research will provide the scientific community with the resources to embark on a new era of targeted immunotherapy.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Dundee

Maintaining the genome of germ cells, exploring and exploiting processes related to recombinational repair in C. elegans 03 Dec 2014

Resolving cruciform DNA structures referred to as Holliday Junctions (HJs) is a critical step inrecombinational repair. We wish to understand how the GEN1 Holliday Junction (HJ) resolvaseworks and how it acts as a DNA damage response signalling molecule. We aim to screen forgenes that act in the gen-1 pathway to mediate DNA double strand break (DSB) repair andcheckpoint signalling. We also intend to find genes that act redundantly with gen-1 to repairDSBs. We will exploit a combination of C. elegans forward genetics and biochemistry, combinedwith complementary experimentation in the chicken DT40 tissue culture model.

Amount: £295,334
Funder: The Wellcome Trust
Recipient: University of Dundee

Deciphering the second messenger regulatory network(s) in Pseudomonas aeruginosa that control persistent infection. 19 Nov 2014

Biofilm formation by P. aeruginosa is central to its establishment of persistent infections, and is itself controlled by the nucleotide second messenger c-di-GMP. My proposed research builds upon work by the host laboratory that showed that the HD-GYP domain hydrolyses c-di-GMP and that all three proteins containing this domain in P. aeruginosa (PA2572, PA4108 and PA4781) have distinct and overlapping roles in biofilm formation and expression of virulence factors. I aim to dissect these signalli ng pathways utilising c-di-GMP and the HD-GYP domains, which are critical to the development of P. aeruginosa persistent infections. To achieve this I will address three questions: 1. What is the scope of regulation by HD-GYP domain proteins in P. aeruginosa? 2. How do PA2572, PA4108 and PA4781 exert their regulatory activity? 3. What is the mode of regulation of biofilm formation by PA2572, PA4108 and PA4781? Addressing these questions will establish the importance of the c-di-GMP signallin g pathway(s) in biofilm formation and other processes related to persistent infection, and could apply to other bacterial pathogens. Furthermore, elucidating the regulatory principles that control the development of biofilms during infection via the c-di-GMP system(s) will be invaluable for targeting the underlying molecular interactions and mechanisms pharmacologically.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Dundee

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £2,250,000
Funder: The Wellcome Trust
Recipient: University of Dundee

University of Dundee - Molecular and Cellular Biology 30 Sep 2016

University of Dundee 4 Year PhD Programme - Molecular and Cellular Biology

Amount: £119,367
Funder: The Wellcome Trust
Recipient: University of Dundee

The Image Data Resource: Making Biological Imaging Data FAIR 05 Jul 2018

We have built the Image Data Resource (IDR; http://idr.openmicroscopy.org; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536224/), an added value database prototype that publishes and integrates scientific image datasets linked to peer-reviewed publications. As of this writing, IDR publishes > 45 TB of image data, > 1.0 million experiments, and > 37 million image planes in 46 published studies. The resource is accessed by more than 1600 unique users per month, generating > 1 million hits/month. Under the proposed Biomedical Resource Award, we will continue growing IDR, taking in more and more diverse imaging datasets, and scaling the computational resources that enable online, cloud-based computation, querying and re-analysis of IDR datasets. A major focus of this project is the engagement with a range of biologists, image analysts and computational biologists through our participation in NEUBIAS, Euro-BioImaging and Global BioImaging to test new User Interface and Experience concepts to substantially grow the interaction and accessibility of IDR and its data. We will leverage EMBL-EBI’s extensive community/training resources to hold several user testing and training sessions to achieve this aim.

Amount: £1,323,597
Funder: The Wellcome Trust
Recipient: University of Dundee

Molecular mechanisms responding to DNA damage and replication stress at the replication fork 11 Nov 2015

There are two major strands to my proposed research. First, I aim to establish direct molecular connections between different DNA damage response (DDR) proteins linked to nephronophthisis-related ciliopathies (NPHP-RC). Second, I aim to understand how the DDR interfaces with other cellular pathways to drive morphological defects relevant to disease progression observed in a 3D kidney spheroid model system. To address the first aim, I will monitor genetic and protein interactions between DDR fact ors of interest sharing similar molecular functions and disease phenotype. This will determine if these factors collaborate in a common DDR pathway. To address the second aim, I will determine if key phenotypes of interest are observed concomitant with kidney spheroid morphology defects. Specifically, I will ask if apoptosis, senescence or epithelial-to-mesenchymal transition are elevated upon DDR activation, and probe the importance of these in spheroid dysfunction by genetic rescue experiments . In parallel, I will use unbiased genetic and proteomic screens to determine the major effectors of DDR proteins linked to NPHP, and validate these hits as causative of DDR-induced defects in spheroid assays. These parallel approaches will significantly expand our understanding of the molecular basis of the NPHP-RC phenotype associated with mutations in specific DDR proteins.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Dundee

A pipeline of drugs for leishmaniasis and Chagas disease 21 Nov 2016

Visceral leishmaniasis and Chagas disease are neglected tropical diseases that cause substantial suffering and an estimated 60,000 deaths each year. Current medicines are inadequate – issues include limited efficacy and unacceptable toxicity. There is a need for new, effective and safe drugs to save lives and improve quality of life for people in low-income countries with these diseases. Our fully-integrated team, led by Professor Paul Wyatt, Dr Jose Fiandor and colleagues at the University of Dundee and at GSK has the substantial leadership, experience and infrastructure required to develop drug candidates suitable for clinical trials. We are already making substantial progress: we have identified two candidate drugs for visceral leishmaniasis and improved the methodology and systems to develop drugs for this and Chagas disease. But a greater pipeline of candidate drugs is required to ensure clinical success. Our goal over the next five years is to deliver at least two, potentially three, new drug candidates suitable for clinical trials for either of these diseases.

Amount: £7,454,810
Funder: The Wellcome Trust
Recipient: University of Dundee

Molecular mechanisms of kinetochore motion along a microtubule in early mitosis 23 Jun 2014

To prepare for chromosome segregation in mitosis, chromosomes must be collected to the spindle in an earlier stage of mitosis. This process is dependent on kinetochore-microtubule (KT -MT) interaction: KTs initially interact with the lateral side of a MT and move along the MT (KT sliding) towards the spindle. KT sliding is driven by KT-associated MT-minus end-directed motors, dynein in animal cells and Kar3 (Kinesin-14) in budding yeast. However, detailed mechanisms of KT sliding are not yet known. Here, I will address how Kar3 drives KT sliding along a MT in early mitosis, using budding yeast as a model organism. I will elucidate what conformation Kar3 takes (homodimer or heterodimer) at KTs, how such conformation is determined at KTs and how Kar3 is recruited to KTs. I will also recapitulate and characterize Kar3 conformation and function at KTs in vitro, using a single molecule analysis. Kar3 offers a popular model of a MT-minus end-directed kinesin, and my study will shed a new light on how a MTminus end-directed kinesin drives transport of a cargo along a MT. My study will also elucidate molecular mechanisms of KT sliding along a MT that is a biologically important but still elusive process.

Amount: £151,392
Funder: The Wellcome Trust
Recipient: University of Dundee

Investigation of the fundamental crosstalk between HIF-2a, HIF-1b and the NF-kB pathways in hypoxia and inflammation 23 Jun 2014

Recently several studies have demonstrated that hypoxia and inflammation are intimately linked, in particular at the molecular level. In fact, the crosstalk between the two main transcription factors involved in the pathways, Hypoxia Inducible Factors (HIFs) and NF-KB respectively, is extensive. To date the majority of research has focused on the regulation of HIF by NF-KB, whereas the contribution of HIF to the NF-KB pathway is still poorly understood. The Rocha laboratory already identified a role for HIF-1a in restricting the NF-KB pathway in mammalian cells and in Drosophila. However, other preliminary data suggested that, HIF-1 13, when over-expressed, can increase the NF-KB activity, and consequently the immune response in vivo in non-stimulated conditions. The aim of this project is to determine the regulatory role of HIF-113 in the control of the NF-KB pathway, and investigate the molecular interactions between the two factors. In addition, this project aims to elucidate how HIF-2a regulates the NF-KB pathway in hypoxia and inflammation. The biological significance of HIF-2a and/or HIF-1 13 regulation of the NF-KB pathway will be assessed using Drosophila me/anogaster as an in vivo model.

Amount: £151,392
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust Clinical PhD Programme at the University of Dundee: "Genomic investigation into evolution of Staphylococcus aureus and the micro-epidemiology of Staphylococcus aureus in atopic eczema." 14 Apr 2014

Across all continents Staphylococcus aureus is the commonest cause of skin and soft tissue infection. Surface displayed and secreted proteins are fundamental for the ability of this bacterium to colonise and infect human hosts. Such secreted factors confer this organism’s ability to adhere to host cells and evade the immune system. The Type VII protein secretion system (T7SS) in S. aureus is emerging as an important system that contributes to disease-causing mechanism for this human pathogen. It has previously been shown that inactivation of the Type VII system in S. aureus (or equivalent in Mycobacterium) reduces pathogenicity. As of yet the precise function of this secretory system is still not fully understood. The aim of this work is directed towards determining the role the T7SS plays in human skin colonisation and the potential role it has in infection. This will be achieved by studying both T7SS wild type and mutant strains in models of skin infection (murine) and colonisation (ex-vivo human tissue culture). Once the involvement of the T7SS in these models in confirmed we will examine the contribution of the secreted substrates with human cells.

Amount: £243,031
Funder: The Wellcome Trust
Recipient: University of Dundee

Molecular determinants of intraepithelial lymphocyte function in intestinal infection 22 Feb 2017

Intraepithelial lymphocytes (IEL) are the first immune cells that pathogens encounter in the gut. These lymphocytes lie within the epithelial layer, and are central to controlling infection, stress or transformation of the gut epithelium. Despite their importance, we have a poor understanding of how IEL sense and respond to stress in epithelia, partly due to the lack of genetic tools that specifically target IEL. To get unbiased insights into the complex biological processes underlying IEL function, I determined the quantitative proteomes of three main intestinal IEL subsets. This unique dataset reveals that IEL are phenotypically and functionally distinct from conventional T cells. The IEL proteomes provide unprecedented insights into the effector functions of intestinal IEL and suggest new hypotheses of how their function might be regulated. Based on these data, I will (1) explore the apoptotic and non-apoptotic functions of abundantly expressed granzymes in IEL, (2) develop novel genetic tools to dissect the role of IEL in the early immune response to pathogens, and (3) address the contributions of inhibitory receptors and their signalling pathways to IEL homeostasis and sensing of epithelial dysbiosis. In summary, the proposed research will reveal how IEL communicate and respond to bacterial and parasitic infections.

Amount: £1,182,281
Funder: The Wellcome Trust
Recipient: University of Dundee

Molecular mechanisms of DNA replication termination 09 Nov 2016

Eukaryotic cells must duplicate their genome once per cell cycle, to allow genetic information to be accurately propagated during cell division. Defects in genome duplication are a hallmark of the early stages of tumour development, and mature tumours may thus be sensitive to agents that disrupt this process. Chromosome duplication is carried out by a multi-protein assembly termed the replisome, itself a critical determinant of genomic integrity, and a target for current and future anti-cancer therapies. A major focus of the eukaryotic DNA replication field for the past two decades has been understanding the mechanism of replisome assembly during replication initiation. Conversely, almost nothing is known about how the replisome is disassembled once genome duplication is completed. I plan to reconstitute eukaryotic DNA replication from initiation to termination with purified proteins. This reconstitution should facilitate a comprehensive study of the mechanisms and regulation of replisome disassembly, and thus significantly advance our understanding of how the replisome is regulated to preserve genome stability.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Dundee

Centre for Neglected Tropical Diseases Drug Discovery 30 Oct 2016

The vision for the Centre is to help tackle the urgent unmet medical need and lack of drug discovery research for Neglected Tropical Diseases (NTDs) by creating the hub for NTD drug discovery and being the collaborator of choice for academics, Pharma and Product Development Partnerships (PDPs) in the translation of discovery science into drug candidates. The success of this vision will be evidenced by increased integration, efficiency and effectiveness of the discovery science, drug discovery and mode-of-action teams in Dundee, providing: Accelerated delivery of NTD drug candidates for our PDP partners, with an initial focus on visceral leishmaniasis and Chagas' disease. Improved paradigms for carrying out NTD drug discovery, including improved understanding of PKPD relationships and more predictive disease models. Improved methodology to determine drug modes of action and resistance mechanisms. Increased exploitation of novel drug targets through structure based drug discovery, involving collaborators worldwide. Training and support for international scientists in the theory and practice of NTD drug discovery. Increased public engagement and awareness of the impact of, and need for, new medicines for NTDs and a greater understanding of the nature and importance of drug discovery.

Amount: £13,611,794
Funder: The Wellcome Trust
Recipient: University of Dundee

Open access award 2015/16. 21 Sep 2015

Not available

Amount: £168,275
Funder: The Wellcome Trust
Recipient: University of Dundee
Amount: £151,712
Funder: The Wellcome Trust
Recipient: University of Dundee

Inhibition by proxy: targeting fungal chitin synthesis through sugar nucleotide biosynthesis. 13 Nov 2014

A limited therapeutic arsenal against increasing clinical disease due to opportunistic pathogenic fungi necessitates urgent characterisation of novel antifungal targets. The fungal cell wall of Aspergillus fumigatus represents a drug target: this dynamic and multi-layered structure is almost entirely built of polysaccharides such as chitin and glucan that are absent from the host. Chitin synthases convert the sugar nucleotide precursor UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) to a linear core of chitin that is fundamental for survival. A proxy target for chitin synthesis, glucosamine-6-phosphate N-acetyltransferase (Gna1), plays a key role in de novo UDP-GlcNAc biosynthesis. Two equally important hurdles any potential drug target must overcome during initial assessment relate to (1) phenotype and (2) ligandabiilty i.e. are chemical-protein interactions possible? Fragment screening assesses the latter and together with x-ray crystallography I have have discovered a fungal specific bindi ng pocket on the target protein Gna1 next to the active site. In vitro growth of my gna1 knockout is only possible with exogenous GlcNAc. Building on this exciting body of preliminary data with the support of the Wellcome Trust I will investigate: 1. Contribution of GNA1 to pathogenicity using invertebrate and murine infection models. 2. Elaboration of promising hits into inhibitors with in vitro fungicidal activity.

Amount: £275,375
Funder: The Wellcome Trust
Recipient: University of Dundee