- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 31 Mar 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Oral drug delivery using peptide carriers 30 Aug 2006
University Translation Award Oral drug delivery using peptide carriers PepT1 is a protein located in the jejenum region of the small intestine, and (to lesser extents) in specific membranes of other organs (e.g. kidney, lung). PepT1 transports di- and tri-peptides across the wall of the small intestine, and it is the primary mechanism by which nitrogen enters the bloodstream. It is also able to transport certain drugs (e.g. ß-lactams, peptidic ACE inhibitors), but most drugs are not recognised or transported by PepT1. We aim to develop dipeptide analogues that will be recognised and transported by PepT1, and to which drug molecules that are not orally active might be attached. The resulting conjugates are intended to increase the bioavailability of the drug, by facilitating uptake via the PepT1 pathway in the small intestine, followed by release of the active drug by hydrolysis. The commercialisation objectives are: a) Identify the optimum patenting strategy and exemplify the UK priority patent filing through synthesis of relevant dipeptide analogues; b) Identify the best carrier(s) for drug delivery by an extensive structure-activity analysis, and develop the technical know-how to prepare specific drug-carrier conjugates; c) Conduct initial market research to identify the areas of commercial opportunity, and develop a more detailed commercialisation strategy based upon the results.
Functional brain imaging is now an essential tool, and is well-established in medicine. The need for brain imaging is increasing with growing concern over neuro-degenerative diseases, such as Alzheimer’s, hence there are larger numbers of patients to be routinely scanned than ever before. Current scanners are not available in every hospital due to their high cost. Where they are available they are large, noisy, fixed installations that are not portable. Professor Hugh McCann and Dr Chris Pomfrett from the University of Manchester has been awarded translational funding to develop a newly discovered technique called Functional Electrical Impedance Tomography of Evoked Responses (fEITER), which is directly sensitive to the brains electrical operation. This tool will enable screening of large populations, and prompt action to be taken in emergencies. The scans could be performed wherever the patient is, even at home.
Student elective for Martin Scott. 19 Jul 2006
Standardisation and application of multiplex PCR as a rapid diagnostic test for the detection of infectious agents in the intraocular fluids of clinically suspected infectious retinitis patients Aravind Eye Care system is based in Tamil Nadu, South India. The organisation has a network of hospitals throughout the State which, in terms of surgical volume and the number of patients treated, are the most productive eye care centres in the World. Aravind's goal is to eradicate needless blindness based on the philosophy that all patients are afforded the same care and service regardless of their economic status. As well as providing clinical services, Aravind, is also a research institute contributing towards the further development of eye care. My elective project will be based at Aravind's headquarters in Madurai and will comprise part of their microbiological research programme investigating viral retinitis. Aims: 1. To standardise and apply PCR for the detection of Herpes simplex virus, Varicella zoster virus, Cytomegalovirus and Toxoplasma gondii, in the intraocular fluids of patients diagnosed with infectious retinitis. 2. To standardise and apply multiplex PCR technique for rapid identification of the viral agents.
'History of Clinical Iatrogenesis: Before and After Ivan Illich' workshop to be held at the Wellcome Unit for the History of Medicine, University of Manchester on 19th May 2006. 22 May 2006
History of Clinical Iatrogenesis: Before and After Ivan Illich Precisely 30 years ago, the social critic Ivan Illich published his book Medical Nemesis: The Expropriation of Health, in which he presented several cases of iatrogenic diseases as a way to illuminate the intrinsic flaws of highly institutionalised, professionalised, technological modern medicine. He problematised modern medicine because, in his view, it deprived people of illness experiences and simultaneously inhibited autonomous efforts to maintain health. Since the publication of Medical Nemesis, critics from medical sociology, policy and even inside medicine engaged with Illich's ideas of 'iatrogenesis'. In contrast, there has hardly been any debate in the history of medicine. Although adverse effects of medicine had long been noted and commented on inside and outside medicine with words such as 'poisoning' and 'toxicity', the conditions that Ilich referred to as 'iatrogenic' diseases emerged in the post-war period, and they were correlated with the rise of new medical therapies, new technologies, the use of new drugs such as penicillin and cortisone, and surgical techniques such as organ transplantation. The term has resurfaced in the public domain more recently, in the context of morally- and politically-charged discussions over the (re-)emergence of infectious diseases such as MRSA and AIDS. This meeting has emerged from work on the Trust-funded grant on Fungal Diseases and Modern Medicine: Mycology, Aspergillosis and Iatrogenic Diseases.
History of the Colonial Copperbelt Malaria Control Programme in Zambia, 1920-1950 The book length project reconsiders the seminal event in the development of mining on Zambia's Copperbelt, an event that also played a key role in the history of tropical medicine and its uses for industry - the Ross Institute Expedition to the Copperbelt in 1929. On the advice of the Expedition's experts, including William Simpson and Malcolm Watson, mine managers began a sanitation campaign against malaria, dysentery and other diseases. Malaria control proved to be highly successful in this case. I am examining the reasons for the success of the programme, its relevance to today's malaria control efforts in Africa and its interpretation by African miners, mosquito control workers and inhabitants of the Copperbelt. The resulting book, Snake Spirits and Garden Cities: The Moral Economy of Malaria in Colonial Zambia, 1920-1960 requires follow-up work in Zambian archives for its completion.
A Medical History of Blindness 1900-1948. 14 Jun 2006
This project explores the medical history of blindness in Britain between 1900-1948, challenging current historical interpretations that emphasise charity, education and social policy. I argue that blindness became 'medicalised', meaning that it was treated as pathological and as a condition that required expert medical and technological intervention. This, as I show, was a significant reconceptualisation, spurred by new technologies that revealed an individual's visual acuity, allowing ophthalmologists to reassess the physiology of eye itself, and recast blindness as a measurable 'impairment' of normal vision. By the inter-war period, medical experts had classified ever increasing numbers of people as 'visually impaired'. In so doing, these experts simultaneously broadened and deepened the scope for professional intervention, creating new and more specialised treatment regimes for a wider cross-section of the population. Understanding the medicalisation of blindness also reveals the reconfiguration of social and cultural understandings of eyesight, blindness and visual impairment. I situate the medicalisation of blindness in both expert and everyday discourses, ranging from highly technical discussions about retrolental fibroplasia to popular editorialising about 'cinema fatigue'. My work will thus further our understanding of how notions of impairment and perception are shaped by targeted technologies, social environments and cultural constructs.
Structural and functional studies of the torque-generating system of bacterial flagellar motor. 01 Jun 2006
The bacterial flagellar motor is a membrane-embedded molecular machine that rotates helical filaments, providing a propulsive force for bacteria to swim. The stator of the motor contains 8 to 10 circumferentially arranged units thatgenerate a turning force (torque) acting on the FliG ring of the rotor. The rotation is driven by the gradient of hydrogen or sodium (in some bacteria) ions across the cytoplasmic membrane. This research proposal aims to apply a multidisciplinary approach to the fundamental question: what is the molecular mechanism of torque generation, i.e. what are the elementary molecular events that compose the cycle of converting the electrochemical energy of the transmembrane ion gradient into the mechanical energy of the rotor rotation? To address this question, the biophysical and biochemical properties of individual components (MotA and MotB) and domains of the stator unit of the unidirectional motor of Rhodobacter sphaeroides will be investigated in parallel with characterization of the minimal stator unit as a whole, and complemented by structural studies using X-ray and electron crystallography and small angle X-ray and neutron scattering techniques. This work will address the precise role of extramembrane domains in interaction with the peptidoglycan layer, assembly of the stator unit and interaction with FliG, identify the proton pathway and possible mechanisms for the ion selectivity ofthe stator and characterize conformational changes that occur at discrete stages of protons passing through the torque-generating complex. These studiesshould reveal the possible mechanism responsible for the mechanochemical torque generation and allow formulation of a model adequate for further biochemical and physiological testing.
The role of two G protein-coupled receptors in regulating appetite and energy expenditure. 12 Jun 2006
The process of feeding is a relatively automated process, with feed-forward and feedback sensory information from the whole orogastrointestinal tract driving reflex loops and central pattern generators in the brainstem, so that once a meal is started we continue to eat until we reach satiety. While these direct regulators of feeding control the size of an individual meal, this information has to integrate with the indirect regulators of feeding that include metabolic, nutritional, behavioural, rhythmic and social factors. We have postulated a role for two peptides expressed in the brainstem, prolactin-releasing peptide and neuromedin U, to link the direct and indirect regulators of feeding, since they both have profound effects on appetite and energy expenditure. However, due to the lack of antagonists for these peptides, it has been difficult to provide definitive proof of our theory. We now have available two transgenic mouse lines that are deficient in receptors for these peptides, and at least one of these lines has an obese phenotype. Using the mice, and with complementary studies in rats, we will test how the two peptides affect appetite and energy expenditure, and how they impinge on other systems controlling behaviour and circadian rhythms.
The Wellcome Trust Centre for Cell-Matrix Research (WTCCMR) is a multidisciplinary research centre embedded within the Faculty of Life Sciencesat the University of Manchester. The long-term aims of the WTCCMR are to elucidate the structure and function of extracellular matrices (ECM) and theircellular receptors, to define the role of ECM and cell-ECM interactions in normal development and human diseases, and to develop approaches for preventing and treating such diseases. The strategy employed has been to recruit a team of researchers with overlapping interests and complementary skills, and to facilitate their work by providing a physical and technologicalenvironment of the highest standard. Over the next five years, research within the WTCCMR will be packaged into four interlinked programmes - (1) molecular basis and cellular control of ECM assembly, (2) organisation of signalling at the cell-ECM interface, (3) microenvironmental determination of cell fate, and (4) cell-ECM engineering and tissue regeneration. This research plan has been crafted to advance our understanding of the basic mechanisms of ECM function, and to suggest experimental strategies for correcting ECM defects and repairing dysfunctional tissues. This application seeks to renew Centre status and requests funds to support the core infrastructure of the WTCCMR.
Molecular analysis of a genetic switch. 17 Oct 2005
The Saccharomyces cerevisiae GAL genes encode the enzymes of the Leloir pathway. The genes are transcriptionally active when yeast cells are grown in medium containing galactose as the sole source of carbon. Under other carbon source conditions, however, the GAL genes are transcriptionally inert. The switch between inactive and active gene expression is controlled by the interplay of three proteins (the transcriptional activator Gal4p, the transcriptional inhibitor Gal80p and the transcriptional inducer Gal3p) and two small molecules (galactose and ATP). Despite decades of genetic and biochemical analysis, the molecular details by which the switch responds to galactose are poorly understood. Recent advances from my own laboratory have, however, led to extraordinary new insights into the transcriptional control ofthe GAL genes. We have already initiated, and will continue and extend during the course of this award, a structural analysis of the GAL regulatory proteins. In addition, the cellular site of interaction between Gal80p and Gal3p that occurs in the presence of galactose will be determined directly using a combination of biochemical and microscopy analysis. The data generatedduring the course of this award will, finally, determine the precise molecularmechanism of this well-studied genetic switch.
This project investigates the neural basis of semantic memory. We will use transcranial magnetic stimulation (TMS) to assess the specific contributions of various cortical regions to semantic tasks in healthy participants. TMS produces a magnetic field over the scalp that transiently disrupts processing in the underlying cortex. We have selected cortical sites for investigation primarily on the basis of neuropsychological studies. Diverse neural regions are implicated in semantic processing by different patient populations (e.g., dementia, herpes simplex encephalitis and stroke aphasia); our TMS investigations will allow an integration of these literatures with functional neuroimaging. Performance on semantic tasks will be examined before and after ten minutes of low frequency repetitive TMS. Coil location will be confirmed for each subject using structural MR imaging and the influence of TMS at different cortical sites will be compared over several sessions for each participant. We will manipulate (1) input modality (pictures vs. words), (2) output modality (comprehension vs. production of object names), (3) specificity of semantic judgement (e.g., knowledge of animals, dogs and Labradors), (4) category of knowledge (faces vs. animals vs. tools) and (5) the requirement for semantic control, in order to elucidate the neural organisation of semantic memory.
Functional characteristics and associated structural features of mammalian melanopsin photopigments 27 Apr 2006
Melanopsin (a member of the opsin family of G protein coupled receptors) is thought to be the photopigment of recently discovered inner retinal photoreceptors in mammals. To allow direct functional analysis of this protein we have lately developed methods for its heterologous expression in cell culture and shown that, under these conditions, it binds retinal to form a photosensory complex with the ability to regulate cell activity via G-protein signalling. Here we propose building on our heterologous expression breakthrough to conclude a detailed functional and structural analysis of this protein based around 3 goals.Goal 1. To consolidate our functional analysis of human and mouse melanopsins using spectroscopic, physiological and biochemical approaches to elucidate aspects of its photochemistry (especially its spectral sensitivity and photoactivation) and G protein coupling.Goal 2. To generate an accurate 3D structure of melanopsin, based initially upon an empirical computer model, and refined according to experimental examination (cf goal 3) and 2D/3D crystallography.Goal 3. To establish critical structure:function relationships for melanopsin by using our developing structural understanding to define suitable site directed mutants and exposing them to detailed functional analysis.
Function and regulation of the SNAT4 isoform of the System A amino acid transporter in human and mouse placenta. 23 Feb 2006
A wealth of data suggests that the placental System A amino acid transporter is particularly important in supplying the fetus with amino acids necessary for normal growth. Consequently, abnormal activity of this transporter may be the cause of some cases of fetal intrauterine growth restriction (IUGR). There are three different isoforms of System A (SNAT1, 2 and 4) but their relative importance to placental amino acid transport has not been established. Our preliminary data show that, i. contrar y to previous reports, SNAT4 is expressed by the placenta; ii. expression increases over gestation; iii. in a mouse model of IUGR, SNAT4 gene (Slc38a4) expression is related directly to fetal growth. However, the functional role of SNAT4 in the placenta has not been investigated. Our aim is to test the hypothesis that placental SNAT4 is functionally important in transporting specific amino acids required for normal fetal growth. We will test this hypothesis using an integrated biology approach w ith the key goals to determine: i. activity of SNAT4 in human placental trophoblast; ii. functional activity and regulation of SNAT4 in placenta over gestation iii. role of SNAT4 in amino acid supply to the fetus, using a mouse model of IUGR.
Targeting and regulation of kinesin-1. 21 Feb 2006
Although it has been proposed that different kinesin-1 isoforms are targeted to particular cargoes, functional evidence for this hypothesis has been lacking. Using assays in which membrane movement along microtubules is reconstituted in vitro, we have evidence that kinesin light chain (KLC) 1B is involved in rough endoplasmic reticulum (RER) movement, while KLC1D is required for movement of vesicles in a Golgi fraction. So far, all of the proteins identified as kinesin-1 interactors will bind to all forms of kinesin-1. Our first goal, therefore, is to identify and characterise proteins which interact with KLC1B but not KLC1D, and vice versa. Kinesin-1, like other motors, is very likely to be tightly regulated so that the right cargo moves at the right time. Currently, however, we know almost nothing about the way in which kinesin-1 is regulated in non-neuronal cells. Our recent work has revealed a novel role for dynactin in activating kinesin-1-driven RER and Golgi vesicle movement. Dy nactin was first identified as a regulator of cytoplasmic dynein, a microtubule motor which moves in the opposite direction along microtubules compared to kinesin-1. Our second goal is investigate how dynactin regulates kinesin-1 activity.
We propose to study the structure and function of the RNA modifying enzyme thiostrepton resistance methyltransferase (TRMT). TRMT is expressed in the thiostrepton antibiotic producing organism, Streptomyces azureus, to confer resistance by ribose 2 -OH methylation of a single specific nucleotide (A1067) in the large ribosomal subunit rRNA. We will determine the X-ray crystallographic structures of TRMT in various functional states: from the apo enzyme to complexes with S-Adenosyl-L-methionine (A doMet) cofactor (or cofactor product) and/ or rRNA fragments. As a starting point, we have already obtained crystals of the TRMT-rRNA complex (using a 58 nucleotide rRNA domain) that diffract to better than 2.8 resolution, and can be indexed and processed with reasonable statistics. Crystals of other complexes will be obtained through systematic high-throughput crystallisation methods. These studies will also be supported by RNA and protein mutagenesis analysis and further structural studies of antibiotic-rRNA-protein complexes. Our results will address important questions of RNA-protein recognition in RNA modification (vital for selection of the correct target by the enzyme) and the mechanism of RNA modification. While thiostrepton is not a clinically important antibiotic, this work will also provide a good model system for understanding antibiotic resistance via rRNA modification.
The role of memory in SLI: Understanding working, procedural and declarative memory deficits in Specific Language Impairment 04 Jul 2006
This study aims to comprehensively examine memory abilities in children with specific language impairment (SLI). Specifically, this investigation will a) test recent claims that children with SLI have procedural memory difficulties in the context of intact declarative memory abilities and b) compare this position to accounts which view working memory impairments as the primary cause for expressive and receptive difficulties in children with SLI. In addition, the present investigation will examine the relationship between different language deficits and different types or combinations of memory impairments. This approach will include both broad levels of language (i.e. expressive and/or receptive difficulties) as well as more specific areas of difficulty (i.e. vocabulary versus grammatical morphology: past tense "ed"). Fifty children with SLI and fifty non-impaired comparison children aged between 8- 10 years will participate in a number of tasks indexing different aspects of language and memory function. The findings of this project will make a significant theoretical contribution to our understanding of the role memory has in the genesis of the language impairments in SLI as well as having potential to inform practice in terms of specifying in more detail the possible relationship between cognitive difficulties and language functioning in this population.
Investigating snRNA interactions of the GTPase Snu114p required for pre- messenger RNA splicing. 27 Apr 2006
The spliceosome is the RNA/protein complex that carries out pre-mRNA splicing.As splicing is certainly RNA catalysed, determining how proteins of the spliceosome interact with and control the functions of the snRNAs is an essential step in understanding splicing. One protein of the spliceosome, Snu114p, is a GTPase with homology to ribosomal tRNA translocase EF-2. Snu114p is proposed to be involved in U4/U6 snRNA unwinding, release of U1 andU4 snRNPs during spliceosome activation as well as repositioning of U5 snRNA between the two catalytic steps of splicing, similar to EF-2 tRNA repositioning. Little information, however, is available on how Snu114p actually interacts with these snRNAs in the spliceosome. Key goals are 1) produce mutants in Snu114p for tools to investigating how Snu114p interacts with the snRNAs during splicing. 2) Determine the snRNA sequence and structural requirements for interacting with Snu114p. 3) As EF-2 binds and is inhibited by the molecule sordarin, this molecule, and its derivatives, will be tested for binding to Snu114p and inhibition of splicing. This work will reveal how Snu114p interacts and controls the functions of essential RNA components of the spliceosome and may lead to development of a novel small molecule inhibitor of the spliceosome.
Phosphoinositides regulate a number of cellular processes, including membrane traffic, by recruiting various effector proteins to the membrane. Different phosphoinositides are enriched in different compartments, and serve to recruit a specific set of effectors there. In this way phosphoinositides contribute towards giving compartments their functional identity. Lipid kinases and phosphatases modulate phosphoinositide levels and are responsible for maintaining the spatial and temporal regulation of phosphoinositide distribution seen in eukaryotic cells. One such enzyme is Inpp5b, a phosphoinositide phosphatase that is closely related to the OCRL1 protein that is mutated in the X-linked disorder Lowe syndrome. Although Inpp5b has been known for many years, its localisation and function are poorly defined. Recent studies suggest Inpp5b can regulate endocytosis. However, preliminary studies in our lab also suggest a role in the secretory pathway. The aim of this project is to study the precise subcellular localisation of Inpp5b, its interaction with binding partners, and perform functional experiments to evaluate its role in phosphoinositide turnover and membrane dynamics in the secretory pathway. This work will increase our understanding of how phosphoinositides regulate membrane dynamics, and allow us to better appreciate the molecular mechanisms underlying the pathology of Lowe syndrome.
Dynamic interplay of the SUMO and MAP kinase pathways; role of transcriptional integrators in regulating transcriptome readout. 17 Oct 2005
The establishment and subsequent control of specific gene expression programmes in response to extracellular signals, is one of the central processes governing cellular function and identity. The overall aim of our programme is to understand how specific outcomes to signalling pathways are achieved. To do this, we will focuss on studying how responses to MAPK signaling are elicited through differential gene regulation via specific transcription factor-coactivator complexes. To achieve this, we will;· Probe how two novel coactivator/integrator proteins PIASxa and LPP control the activity of ETS-domain transcription factors Elk-1 and PEA3 respectively. · Determine the role of these coactivators in regulating gene expression in a broader context.· Determine how the MAPK and SUMO pathways interact to control the output of MAPK signalling through these complexes.To achieve these aims, we will make extensive use of modern promoter microarray and RNAi-based screening technologies, coupled with bioinformatic techniques to provide an integrated genomics approach to our work. Importantly though, our work will incorporate detailed molecular analysis to complement the genomics-based studies, permitting iterative rounds of hypothesis generation and testing.