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You are what you ate: food lessons from the past 07 May 2010

How did food affect our ancestors? How can we learn from the past to improve our health? This project encourages discussion of modern nutrition in the Yorkshire region by presenting archaeological, visual and textual evidence from the medieval and early-modern periods (12th-17th centuries) to initiate debate and reflection on eating behaviours. Through innovative schools and youth activities, exhibitions, festival attendance, cooking demonstrations, and bone workshops this project explores the concept of a balanced diet in history, encouraging participants to engage with issues that affect their health in the 21st century: obesity, alcohol consumption, dental care, nutritional disorders, growth, famine, the impact of food processing and preservation techniques on diet, the significance of climate change and eating in season, the cost of food, the influence of social status, feasting and fasting, the appearance of food and the concept of taste. The project brings biomedical science, bioarchaeology and medical history to a new audience, working with schools, festivals and museums within the region of Yorkshire and engaging with as much of the local community as possible, especially children, ?hard-to-reach? youth groups and members of different religions and cultures. It encourages discussion of the global context of eating (learning about foods from the New World and past European famines widens awareness of current crises). The project pioneers a new model of public engagement, and will lead to further partnerships between the Universities of Leeds and Bradford and local communities through links with Wakefield Council.

Amount: £176,725
Funder: The Wellcome Trust
Recipient: University of Leeds
Amount: £3,120
Funder: The Wellcome Trust
Recipient: University of Leeds

Switchable Nanostructured Surfaces as a Sophisticated Tool for Cell Biologists. 22 Apr 2010

This proposal is for the development of Switchable Nanostructured Surfaces. These are molecularly well-defined surfaces, which in a highly controlled way can dynamically present biological regulatory signals and stimuli to a cell with nanometre localised resolution. We will exploit principles of self-assembly, molecular shape change and nanofabrication to engineer the tunable biological nanoscale features on macroscopic surface materials. In order to achieve its aim, this project has three centr al objectives: Objective 1 - Development of stimulus-responsive molecular systems for real-time and reversible control of biomolecule activity on large scale surfaces. Objective 2 - Development of a nanopatterning methodology that will allow immobilisation of multiple biologically differing stimuli systems at well-defined and nanoscale locations with a high degree of selectivity. Objective 3 - Test and exploit smart switchable biological nanostructured surfaces to investigate stim ulus-activated calcium concentration [Ca2+]i signalling and cell responses in sperm and how these relate to cell quality .

Amount: £146,176
Funder: The Wellcome Trust
Recipient: University of Leeds

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £15,660
Funder: The Wellcome Trust
Recipient: University of Leeds

Value in People Award. 29 Mar 2010

Not available

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

Open access award. 22 Sep 2009

Not available

Amount: £45,000
Funder: The Wellcome Trust
Recipient: University of Leeds

Time-resolved X-ray crystallography. 21 Apr 2009

1) Develop a statistical approach to distinguish coherent (functionally related) and incoherent (noise) structural changes in time-resolved crystallographic data. 2) Develop the use of single crystal spectroscopy to provide time-resolved ' spectroscopic data correlated with the diffraction experiment : 3) Combine QM/MM (quantum mechanics/molecular mechanics) simulations with the experimentally determined time-resolved structures to yield a full, experimentally restrained, structural and dynamic description of macromolecular function.

Amount: £142,657
Funder: The Wellcome Trust
Recipient: University of Leeds

Protein recognition and dynamics in the early steps of aggregation 21 Apr 2009

In this study, we propose to use modern NMR and molecular dynamics (MD) simulations to investigate the dynamics of ?2m and to explore the role of further conformational changes of ?N6 in the early stages of protein aggregation. Specifically we aim to: 1. Study the dynamics of 132m in vitro, using NMR relaxation dispersion experiments, to understand the transition from the folded structure of t.N6 to species with enhanced amyloidogenic properties. 2. Use Paramagnetic Relaxation Enhancement (PRE) technique1s to characterise transient lowly populated dimerisation events that occur in the early stages of t.N6 aggregation. 3. Use molecular dynamics simulations to characterise local flexibility of l32m and expand our understanding of the amyloid formation pathway.

Amount: £142,657
Funder: The Wellcome Trust
Recipient: University of Leeds

Mechanisms used by multisegmented dsRNA animal viruses in counting and selecting genomic segments during replication 21 Apr 2009

Recent advances in reverse genetics of dsRNA viruses have shed light on some aspects of genome packaging, yet the question of genome segment counting is not resolved. There is no available in vitro re-assembly system for animal dsRNA viruses, mostly because of the complexity of the viral protein-protein, protein-RNA and RNA-RNA interactions involved in virus particle formation. Genomic RNA may play pivotal roles in the assembly and sorting of genome segments. The proposed research project will investigate the mechanisms of segmented genome encapsidation by animal dsRNA viruses using 2 model systems: avian reovirus and infectious bursal disease virus (IBDV). These viruses are important poultry pathogens worldwide, and are convenient and relevant models for understanding dsRNA virus assembly. Avian reovirus with its genomic segments has much in common with other mammalian reoviruses and rotaviruses, while the structure of IBDV has been extensively characterized, although nothing is known about the mechanisms of its RNA packaging. Moreover, recent experimental data suggest that IBDV two-segmented genomic RNA packaging lacks the tight selective (1control typical for rotaviruses and reoviruses, and comparative studies may help our further understanding of the structural basis for selective packaging of dsRNA viral genomes. The specific objectives of the project are: 1) To map specific protein-RNA and RNA-RNA interactions involved in virus genome packaging; 2) To establish in vitro virus assembly assays based on the data from objective 1 and to characterize assembly intermediates in real-time. 3) To develop in vivo assembly assays for our model viruses and to test the predictions from the in vitro studies of the virus particle formation and genome encapsidation.

Amount: £142,657
Funder: The Wellcome Trust
Recipient: University of Leeds

Engineering of galactose oxidase substrate specificity 21 Apr 2009

Amadori-modification of serum proteins occurs at much higher levels in diabetic patients than in normal individuals and the resulting glycation can lead to a number of complications such as atherosclerosis and cataract formation (1). Accurate monitoring of serum protein glycation may enable diagnosis of diabetes in its early stages. Galactose oxidase (GO) from the fungus Fusarium graminearum has been extensively characterised and shown to have a solvent accessible active site and broad substrate specificity making it an ideal candidate for the introduction of activity with new substrates. Following further characterisation of the enzyme to broaden our understanding of key residues, we aim to engineer GO to accept glycated serum albumin as a substrate in order to enable future development of a biosensor to be used in the diagnosis of diabetes. We also aim to introduce activity against other sugar substrates with potential uses in chemical synthesis and pharmaceutical industries. Objective 1) Develop an agar plate-based assay to screen colonies containing mutants of GO for oxidase activity. Objective 2) Determine crystallisation conditions for E. coli-expressed GO. Objective 3) Explore the role of selected second sphere residues in the catalytic function and substrate specificity of GO. Objective 4) Through modification of active site loop regions, engineer the enzyme to accept alternative substrates, including Amadori-modified serum proteins which are elevated in diabetic patients.

Amount: £142,657
Funder: The Wellcome Trust
Recipient: University of Leeds

Designing protein-protein interfaces in Cholera Toxin for synthetic virus-like capsid construction 21 Apr 2009

1. Identify mutable residues in the CTB structure across the proposed interaction surface, which maintains pentameric stability and sugar binding capacity. 2. Use computational modelling to make suggestions as to which residues to mutate to increase pentamer-pentamer binding propensity. 3. Develop aptamers to the A--subunit binding face of CTB as part of developing an ITC/AUC based technique to measure cooperative binding events and detect :weak repulsion or attraction. Structural evaluation of aggregates formed.

Amount: £142,657
Funder: The Wellcome Trust
Recipient: University of Leeds

Engineering Solutions for an Ageing Population with Musculoskeletal & Cardiovascular Disease. 50 more years after 50. 23 Mar 2009

The   ageing population is increasing in number and life expectancy. The population   expects fifty more years after fifty with high levels of activity and quality   of life. However, the musculoskeletal and cardiovascular systems age and   degenerate, adversely affecting mobility, ability to work and quality of   life. Advances in engineering and bioscience have created opportunities for   novel devices and regenerative therapies, which utilise innovative   biomaterials or biological scaffolds to guide the patient's own stem cells to   repair degenerative tissues. Advances in patient imaging and diagnostics are   enabling earlier disease diagnosis with opportunities to intervene earlier in   the degenerative process and preserve healthy tissue, and potential to   provide patient specific continuum of care. WELMEC will deliver: - Longer   lasting joint replacements in the hip, knee and spine. - Novel regenerative   biological scaffolds for degenerative joint tissues, dental reconstructions   and cardiovascular surgery. - Advances in cell therapies using the patient's   stem cells. - Advanced medical imaging to facilitate earlier diagnosis and   intervention. - Novel protein biosensors for disease diagnosis and improved   patient targeting. WELMEC will integrate over 200 engineering, physical   science, life science and medical researchers with clinicians and   industrialists to develop and deliver innovative therapies and patient   services for the ageing population.

Amount: £7,456,503
Funder: The Wellcome Trust
Recipient: University of Leeds

VEGFR1 localisation to the Golgi apparatus a novel mechanism regulating endothelial physiology 30 Jun 2009

Vascular endothelial growth factor A (VEGF-A) regulates new blood vessel formation, blood pressure control and disease states such as atherosclerosis, hypertension and tumour metastasis. The VEGFR1 (Flt-1) gene product is a receptor tyrosine kinase that binds to VEGF-A but its exact role in regulating vascular physiology remains unclear. We have discovered that VEGFR1 is localised to the Golgi apparatus and can be translocated to the plasma membrane upon elevation of cytosolic calcium ions. What is the mechanism underlying this phenomenon and how does this relate to the endothelial response to growth factors such as VEGF-A or placental growth factor (PlGF-1)? We will map VEGFR1 sequences that mediate Golgi localisation and utilise this information to manipulate VEGFR1 distribution to assess effects on endothelial signalling and migration. Proteomic and yeast-based analyses will be used to identify VEGFR1-specific interactions. Such gene products will be tested for ubiquitous and calciu m-sensitive interactions with VEGFR1. The roles of VEGFR1-associated proteins in regulating endothelial function will be determined using RNAi to assess their involvement in intracellular signalling, cell migration, cell proliferation and angiogenesis.

Amount: £128,470
Funder: The Wellcome Trust
Recipient: University of Leeds

Structural modulation of amyloid fibrils and intermediates by glycosaminoglycans. 28 Apr 2009

We propose to explore how the molecular mechanism of assembly of disease-linked amyloid species are influenced by glycosaminoglycans (GAGs). We will focus on two important examples of disease-linked amyloid, namely, amylin, associated with type-2 diabetes mellitus, and Abeta1-40, associated with Alzheimer's disease. Solid-state NMR will be used to compare the structure of oligomeric and fibrillar aggregates formed from isotopically labelled peptides assembled with/without heparan sulphate (HS) a nd various GAG analogues. The key goals are: 1. To determine how the presence of GAGs during fibril growth affects the structure of amyloid protofilaments of Abeta and amylin. 2. To identify and describe in atomistic detail the nature of the molecular recognition event between amyloid fibrils of amylin and Abeta with different structural architectures and the GAGs heparin and heparin sulphate (HS). This will be achieved by measuring couplings between isotope labels strategically placed in the peptide precursors and using novel heparan sulphate derivatives prepared by chemically modification to incorporate isotope labels. 3. To examine the effect of GAGs on the mechanism of assembly of amylin and Abeta into amyloid fibrils by the characterisation of transient oligomeric intermediates trapped using rapid freeze-quench followed by their structural analysis using solid state NMR.

Amount: £241,226
Funder: The Wellcome Trust
Recipient: University of Leeds

Transcriptional control of multinucleated giant cells and osteoclasts. 25 Feb 2009

Macrophages are able to fuse and differentiate into either multinucleate giant cells (MGCs) at sites of chronic inflammation or osteoclasts within the bone. However, the molecular mechanisms that control this developmental process remain elusive. We utilize a tractable cellular system for analyzing the gene regulatory networks that underlie macrophage differentiation. By genome wide expression analysis we identify the Hic-5 nuclear co-activator as transiently induced during macrophage developm ent. Targeting of Hic-5 by shRNA diverted macrophage precursors to differentiate along the MGC cell fate. Ectopic expression of Hic-5 within bone marrow derived macrophages resulted in the loss of osteoclast development. By these loss and gain of function approaches we demonstrate Hic-5 as a novel cell fate determinant in repressing the MGCs and osteoclasts cell fates during macrophage development. As Hic-5 binds to DNA indirectly, through protein-protein interactions, we propose to use ChIP-S eq in conjunction with bio-informatics to identify this protein partner. Secondly, we shall establish the requirement of Hic-5 for the development of macrophages by the generation of mice containing a conditionally floxed Hic-5 allele. The accomplishment of these research aims will be of fundamental importance in the greater understanding in the pathology of chronic inflammation and bone disorders.

Amount: £316,007
Funder: The Wellcome Trust
Recipient: University of Leeds

Why does ageing encourage the cardiac pacemaker to fail? 11 Feb 2009

This work will take advantage of recent advances in the understanding of how the cardiac pacemaker works and preliminary data revealing why it might fail in order to gain mechanistic insight into why pacemaker dysfunction is prevalent in the elderly. Cardiac pacemaker dysfunction increases in incidence in an age-dependent manner, even with apparently healthy ageing. This necessitates treatment using artificial pacemakers to prevent the associated incidence of sudden death, exercise intolerance and atrial arrhythmias. An associated problem is an age-dependent reduction in pacemaker response to adrenergic stimulation reducing cardiac responsiveness to stress. Using a rat model of ageing changes in the expression and activity of key proteins involved in cardiac pacemaking will be mapped across the lifespan. Key aspects to be investigated are: 1) Whether processes involved in the new theory of cardiac pacemaking, regulating spontaneous releases of intracellular calcium, change with age . 2) Whether other classical moderators of pacemaker function are changing with age. 3) Whether the decline in response to adrenergic stimulation is due to changes in the phosphorylation response of specific proteins involved in the regulation of depolarisation. 4) Can changes in the activity of specific protein kinases be correlated with age-dependent changes offering routes to intervention?

Amount: £74,993
Funder: The Wellcome Trust
Recipient: University of Leeds

A novel role of the KSHV ORF57 protein in translation enhancement. 02 Oct 2008

KSHV is the most recently identified human tumour virus. It is the etiological agent of all forms of Kaposi s sarcoma. KSHV has two distinct forms of infection, latency and lytic replication. Although latency has been implicated in tumourigenesis, lytic replication plays an important part in the pathogenesis and spread of KSHV infection. Therefore, for a better understanding of KSHV pathogenesis it is essential to study the molecular mechanisms which regulate lytic gene expression and replicatio n. The KSHV ORF57 protein plays a pivotal role in KSHV mRNA processing. It binds intronless KSHV mRNAs and recruits the cellular hTREX complex which in turn allows efficient nuclear export of intronless viral transcripts. We now wish to investigate a second function of KSHV ORF57, namely its role in the translation enhancement of intronless viral transcripts. Specifically we aim to determine whether KSHV ORF57 functions in translation enhancement by recruiting essential cellular translation factors, such as the 48S preinitiation complex, via an interaction with the cellular protein PYM. Moreover, we will determine how KSHV ORF57 regulates the ability to interact with two separate multiple protein cellular complexes, namely hTREX and the PYM/48S preinitiation complex, to perform its multiple functions.

Amount: £120,719
Funder: The Wellcome Trust
Recipient: University of Leeds

The effect of maternal iron status and intake during pregnancy on cardiovascular disease risk in the offspring. 25 Mar 2009

Mother's diet during pregnancy plays an essential role in early foetal development. There is no satisfactory epidemiological evidence to date investigating the relationship between maternal iron during pregnancy, and cardiovascular outcomes in the adult offspring. This project aims to assess the effect of both maternal iron status, measured by serum transferrin receptor to serum ferritin ratio, and iron intake during pregnancy, from diet and supplements, on offspring outcomes. These include blood pressure and weight in the adult offspring, and infant outcomes including birthweight. There is substantial evidence of increased cardiovascular risk with low birthweight. Therefore, the relationship between maternal iron and cardiovascular risk in the offspring will be tested to assess if it is direct or mediated by birthweight. This will be achieved using both prospective and historical cohort designs. Data from three prospective birth cohorts will be used to examine the effect of mat ernal iron intake and status on infant outcomes. Using historical cohort design, the offspring of women with a C282Y mutation, who have higher iron stores than the general population, will be recruited. Their blood pressure, body mass index and waist circumference will be measured and compared to the offspring of women with a wild type gene.

Amount: £254,589
Funder: The Wellcome Trust
Recipient: University of Leeds

Biomedical vacation scholarship. 29 May 2009

Not available

Amount: £7,200
Funder: The Wellcome Trust
Recipient: University of Leeds

Value in people award. 21 Oct 2008

Not available

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