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Results

A systems approach for understanding cell surface dynamics in trypanosomes 30 Nov 2016

The surface membrane and endosomal system of protozoan pathogens directly interfaces with the host; mediated functions including immune evasion, environmental motoring and drug interactions. Recently it has emerged that surface composition and the mechanisms controlling membrane protein turnover in trypanosomatids are highly divergent, and that these processes also are connected with drug interactions. We have clear evidence for complex control based around ubiquitylation, but the roles of many surface proteins remain cryptic. I propose a program of work to integrate, in a system wide manner, how these novel aspects of biology converge to maintain the parasite surface. 1. Examine the mechanisms of ISG and AQP turnover,2. Evaluate the potential of ISGs for novel anti-trypanosome drug delivery,3. Assess the essentiality of ISG protein families in vitro and in vivo using genome editing.4. Refine our understanding of the clathrin and ESCRT sorting systems of trypanosomes to determine how these processes mediate the transport of ISGs, AQPs and the surface proteome in general. Each of these aspects will exploit a combination of state of the art proteomics, super-resolution microscopy and novel genetic tools to understand in greater detail the importance of surface proteins to trypanosome biology, virulence and infectivity.

Amount: £1,393,659
Funder: The Wellcome Trust
Recipient: University of Dundee

The role of MINK1 in homoeostasis of the intestinal epithelium 30 Sep 2018

Surgery and chemotherapy, which preferentially kills dividing cells, are the main treatments for colon cancer: a common disease in the developed world. To develop better treatments requires defining the molecular events that cause tumours to grow so that these specific aberrations can be bypassed. Mutations in a gene called Adenomatous polyposis coli (Apc) are the most common molecular change identified in colon tumours. The Näthke lab recently discovered that APC protein (encoded by the Apc gene) binds to and regulates the abundance of another protein (MINK1) with roles in cell division and movement. This raises the possibility that faulty control of MINK1 by mutated APC could explain why cells in colon tumours divide excessively and migrate aberrantly. I will investigate the function and control of MINK1. Using cells grown in dishes and also cells that form mini-gut structures called organoids, experiments will be designed to determine whether and how MINK1 is required for Apc mutations to cause cancer, and how MINK1 affects the structure of the gut lining. These issues will also be addressed in mice whose guts lack the Mink1 gene. Results will help to decide whether human colon cancer can be treated by new drugs that target MINK1.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Dundee

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £160,456
Funder: The Wellcome Trust
Recipient: University of Dundee

The Role of Salt Inducible Kinase-2 in the Development of Cardiovascular Disease. 27 Apr 2017

Development of Cardiovascular Disease (CVD) is preceded by endothelial dysfunction, inflammation and infiltration of vessel walls by pro-inflammatory leukocytes, resulting in formation of atherosclerotic plaques. Recent in vivo studies have suggested a role for the Salt Inducible Kinase-2 (SIK2) enzyme in regulation of inflammatory cytokine production. SIK2 phosphorylates CRTC3, promoting cytosolic retention. Inhibition of SIK2 prevents CRTC3 sequestration and promotes nuclear accumulation where it associates with CREB and promotes transcription of IL-10, IL-1ra and the anti-atherosclerosis associated gene, Nur77. Furthermore, macrophages from SIK2 kinase-null mice produce significantly less pro-inflammatory IL-6, IL-12 and TNF-a. The precise role of SIK2 in CVD is unknown. Using femoral artery cross-sections and subcutaneous blood vessels collected from diabetic humans following elected above knee amputations, we aim to characterise the expression and function of SIK2 in the development of atherosclerosis. Furthermore, we aim to compare these findings with blood biomarkers of inflammation and kidney function. Expression of SIK2 shall be investigated using RT-PCR gene expression analysis and related to enzyme function using western blot analysis of protein phosphorylation, focussing on the TLR4-MAPK-MSK-CREB-CRTC3 signalling axis. Identification of SIK2 as a regulator of atherosclerotic development could provide a novel drug target for the prevention and management of CVD.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Dundee

Changes in metabolic signalling in a mouse model of Alzheimer's disease 27 Apr 2017

The protease, BACE1 (beta-site amyloid precursor protein (APP)-cleaving enzyme 1) is rate-limiting in amyloid beta (Ab) production. Ab peptides are prone to aggregation causing amyloid plaques, a process strongly linked to Alzheimer’s disease (AD). People with AD have an increased risk of T2D (Janson et al., 2004) and people with peripheral insulin resistance correlate with AD risk (Li & Hölscher 2007). Central obesity also increases dementia risk, independently of diabetes (Luchsinger 2010). Thus, the pathological processes underlying AD are linked with the metabolic disturbances associated with T2D and obesity. We hypothesise that raised BACE1 activity driven by high fat feeding results in the induction of central insulin and leptin resistance and disordered glucose and lipid metabolism, increasing susceptibility to diabetes and cardiovascular disorders. Key Goals By proteomics determine which brain proteins in hippocampus and hypothalamus are up- or down-regulated in a BACE1-dependent manner following chronic high fat feeding. Validate the top proteomic hits by immunoblotting, mRNA and/or ELISA analysis in the appropriate brain areas. Attempt to correlate changes in key signalling pathways with the phenotypic and metabolic characteristics of BACE1 null (resistant to obesity and diabetes) and BACE1-knock-in (increased susceptibility to diabetes) mice.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Dundee

Micro-Metagenomics: Exploring the Application of Microfluidics to Viral Diagnostics 27 Apr 2017

The ultimate goal of the research is to develop a microfluidic system, usable in labratory and field situations, for the detection and quantification of the viral diversity in a sample. The initial stage will focus on analysing viral properties in order to differentiate the viruses into their different families. This data, which focuses on the size, shape and deformability of the viruses, will be used to inform mathematical modelling which will lead to the selection of nano scale filters to be used for testing. Analysis will then be performed on microfluidic experiments to validate models and test the effectiveness and efficiency of the filters when used for viral separation. For this research we will use easy to handle and non pathogenic viruses, as well as control substances with known proportions of these different viruses to allow us to effectively evaluate our initial systems. This will also be complemented by modelling of the particles as they interact with the filters to further investigate the dynamics and properties of separation. A key aim of this research is to generate a wealth of data which will have applications in the viral detection at low concentrations in bodily fluids and unbiased characterisation of viruses.

Amount: £0
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

Fluorescence activated cell sorting for cell biology and immunology 16 Jun 2016

This is an application to support the purchase of a Fluorescence Activated Cell Sorter (FACS) housed in a Biological Safety Containment Level 2 cabinet and to support the salary of a Flow Cytometry Operator. This equipment will support the research of approximately 30 academic research groups within the School of Life Sciences including 21 Wellcome Trust funded Principal Investigators. The research by these groups includes cell and molecular biology, bacteriology, immunology, mammalian developmental biology, parasitology and drug discovery. A dominant focus is on cell signaling, particularly in the context of the immune system, the regulation of cell metabolism and neuro-degeneration. There are also projects involving bacteria, yeast, trypanosomes and leishmania, as well as multiple non immune mammalian cells. The requirement for a new FACS stems from increased usage in research projects, a large increase in demand for use of single cell sorting cell sorting as part of efficient and CRISPR/Cas9 gene editing protocols. There is also the need to use Biological Safety Containment level 2 for cell sorting to allow translation of research ideas generated using model organisms to studies of freshly isolated human blood derived lymphocytes and other human cells.

Amount: £165,000
Funder: The Wellcome Trust
Recipient: University of Dundee

An investigation of the therapeutic potential of a novel marker of tumourigenesis 01 Apr 2016

Aims To establish whether an unusual splicing event of CRMP2 contributes to tumourigenesis. Learn how to carry out scientific research and basic laboratory skills Approaches: I will learn how to culture tumour cells, fractionate sub-cellular components and identify expression of different variants of CRMP2 in each compartment. Further to this, I will learn how to clone different forms of CRMP2 and express these in cells. The project will then move to the generation of novel cell lines where the unusual splice variant of CRMP2 is removed from tumour cells that express it, and increased in cells that do not contain it. This will allow the investigation of the sufficiency and dependency of CRMP2 on tumour cell growth. All of the tools and techniques required are established in the host laboratory.

Amount: £2,000
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

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

Investigation into the regulation of NICD stability and its role in determining the periodicity of the vertebrate segmentation clock 30 Sep 2016

Notch is one of the five major signalling pathways that regulate vertebrate and invertebrate development. Notch signalling relies on cell-cell contact as both ligand and receptor are transmembrane proteins. Upon ligand activation the intracellular domain of the receptor (NICD) is cleaved and translocates to the nucleus to activate gene transcription. NICD is extremely labile and phosphorylation allows this target to be recognised by the F-box protein Fbxw7 which then recruits the Skp1-Cui1-F-box protein (SCF) ubiquitin ligase complex that targets NICD for degradation. Thus, phosphorylation is a key event in NICD turnover but the details of this process remain obscure. Recent work in the lab has shown that a number of different small molecule kinase inhibitors, which delay the vertebrate segmentation clock, also lead to elevated NICD levels and prolonged NICD half-life. This research project aims to determine whether these inhibitors increase levels/half-life of NICD by changing NICD phosphorylation status and whether they affect the interaction of NICD with Fbxw7. We will employ a transgenic mouse that allows real time imaging of clock gene oscillations in tissue explant assays and will use CRISPR/Cas9 knock-in technology to generate NICD phospho-mutants to determine if this alters the periodicity of clock gene oscillations.

Amount: £18,460
Funder: The Wellcome Trust
Recipient: University of Dundee

Extending The Jalview Resource for Biological Sequence Alignment and Analysis. 08 May 2013

Jalview (www.jalview.org) is a free software system for the analysis, editing and visualisation of biological sequence data. It has been developed continuously since 1996. As an applet it is central to hundreds of web resources including those from the EBI and the Sanger Institute. The Jalview Desktop Application is started over 22,000 times per month by users in more than 100 countries. With the massive expansion in sequencing brought about by Next Generation technologies, the need for a too l like Jalview to help interpret the data and put it into functional context has never been higher. In addition to sophisticated multiple sequence alignment editing functions, Jalview provides linked views of phylogenetic trees, DNA and protein sequences, and protein three-dimensional structures. It communicates with remote servers via SOAP and REST protocols for CPU intensive analyses. Jalview currently has funding until Sept 2014 for a single research assistant, who handles software developm ent, support and training/outreach. Here we request additional staff to make Jalview development, bug fixing and dissemination more resilient and responsive so that it can meet the demands of its substantial user community in the face of new sequence analysis challenges.

Amount: £842,437
Funder: The Wellcome Trust
Recipient: University of Dundee

Molecular mechanisms of encystation and sporulation. 26 Nov 2012

Most protozoa survive environmental stress by encapsulating to form a cyst or spore. This process is medically important for pathogenic protists since cysts are resistant to immune clearance, antibiotics and biocides. Cysts of bacterivorous protists such as Acanthamoeba additionally act as vectors for airborne dispersal of bacterial pathogens, such as Legionella pneumoniae, Vibrio cholerae and MRSA. Due to the limited genetic tractibility of encysting organisms, the mechanisms controlling encyst ation are largely unknown. Dictyostelid social amoebas survive stress by building fruiting structures with encapsulated spores and stalk cells. Both cell types mature in response to PKA activation, and we showed that this process is derived from encystation in solitary amoebas, which we found to also require cAMP acting on PKA. The encysting Dictyostelid Polysphondylium pallidum is uniquely suitable for both reverse and forward genetic approaches, allowing us to identify several encystation gene s, which proved to be deeply conserved in protozoa. This included one suitable target for anti-encystation drug development, which we are currently exploring in collaboration with the Dundee Drug Discovery Unit. In our future research we will combine the power of genetics with proteomics and drug development to achieve the following goals: Find all genes that control encystation in P.pallidum and the order in which they interact. Investigate functional conservation of essential genes in path ogenic protists and instigate compound screens to find inhibitors. Identify missing links in the pathways that regulate spore and stalk cell encapsulation in Dictyostelia and establish how these pathways emerged from the ancestral encystation pathway.

Amount: £1,428,543
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust Clinical PhD Programme at the University of Dundee: 'Development of novel models for the study of hepatic insulin resistance as a means to an early diagnosis and treatment for diabetes'. 11 Apr 2011

Reduced tissue sensitivity to insulin, called insulin resistance (IR), is a major feature of Type 2 Diabetes (T2DM). It also develops many years in advance before T2DM. The majority of the health problems associated with diabetes, such as vascular disease, are likely to begin to develop during insulin resistance. Therefore, it is important to understand why and how insulin resistance develops and how it progresses to diabetes and its complications in some people but not others. Insulin reduces hepatic glucose output in large part by repressing transcription of specific genes, but this process is defective in IR and T2DM. We will generate a transgenic mouse expressing a reporter peptide under the control of a key insulin-regulated gene promoter to investigate hepatic IR and its role in development of T2DM. This peptide is secreted into the blood and urine, and is quantified by ELISA. Therefore peptide levels will be directly related to promoter activity and hence be a surrogate of IR. Peptide measurements will be compared with current methods of assessing IR, including gold standard hormone clamp studies. The novel mouse will be made available, for crossing with models of diabetes, providing a non-invasive, accurate technique for the assessment of IR in vivo. These tools will improve research into the development of IR and T2DM.

Amount: £37,659
Funder: The Wellcome Trust
Recipient: University of Dundee