- Total grants
- Total funders
- Total recipients
- Earliest award date
- 23 Jan 2006
- Latest award date
- 13 Dec 2006
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Our key goals are to determine which subpopulations of mouse and human satellite cells are the best muscle stem cells and whether non-satellite cells can contribute efficiently to skeletal muscle regeneration. We will also determine optimal environmental conditions for skeletal muscle regeneration from transplanted satellite or stem cells. We wish to use our model of skeletal muscle formation in vivo from transplanted cells to test the efficacy of potential treatments of Duchenne muscular d ystrophy on human muscle in vivo. We will determine the role of nitric oxide in either preventing or reducing intestinal damage in a rat model of necrotizing enterocolitis. We will also determine the role of stem cells in enhancing tissue repair in necrotizing enterocolitis.
Keeping track of goals is vitally important for survival, particularly if the goals are locations in the world where we can find food or shelter. In order to navigate to these goals we need to know where we are and where the goals are. Whereas considerable evidence suggests that the hippocampus provides a signal for our current location, the neural coding of goal-relevant information is much less certain. Recent evidence suggests that the medial prefrontal cortex may represent goal locations, bu t how it interacts with the hippocampus to achieve this remains an open question. Moreover, the mechanism by which goals are represented in different environmental contexts has not been explored. The proposed research will use single neuron recording, reversible brain inactivation and behaviour in rats to explore how hippocampal and prefrontal regions interact in producing spatially guided behaviour. Different spatial tasks will be used to assess how the medial prefrontal cells signal informatio n about goal locations, allow the animal to switch between navigation strategies and provide a feedback signal to the hippocampus about future goals. The results will enhance our understanding of how the hippocampus and prefrontal cortex contribute individually, and through functional interactions, to the representation of goal-related information.
Regulation of a novel mirror-symmetric cell nervousdivision in the vertebrate nervous system. 12 Oct 2006
Regulation of a novel mirror-symmetric cell division in the vertebrate nervous system To analyse the regulation of the zebrafish C-division (a novel mirror-symmetric division). Previous work suggests that the C-division is regulated by a timing mechanism, not its environment. Other work also suggests that this is the case, as this division is most often number sixteen after fertilisation (Kimmel et al, 1994). Therefore it is possible that cells are either able to measure developmental time or able to "count" the number of divisions. Cell intrinsic programmes of development that may rely on timing mechanisms have been proposed to operate in other neural progenitors both in invertebrates (Luer and Technau 1992, Grosskortenhaus et al 2005) and vertebrates (Qian et al 1998, 2000, Cayouette et al 2003, Shen et al 2006). This project will test the hypothesis that the C-division is regulated by a timing mechanism possibly related to cell cycle number.
The role of electrical activity in the refinement of the Climbing Fiber-to- Purkinje Cell synapse. 12 Oct 2006
The role of electrical activity in the refinement of the Climbing Fibre-to-Purkinje Cell synapse The main aim of this project is to understand the role of activity in refinement of neuronal connections during development. This question will be addressed at a defined synapse in the mammalian brain, the climbing fibre (CF) to Purkinje cell (PC) synapse of the cerebellum, where innervation by multiple CFs gives way to monoinnervation in the adult. I will use a combination of electrophysiological, molecular and imaging approaches, applied both in vitro and in vivo. Specifically, I will determine: The role of presynaptic activity in CF synapse elimination The role of postsynaptic activity in CF synapse elimination The short-term dynamics of CF elimination by visualising multiple CF's in vivo
Determinants of cardiovascular diseases in Eastern Europe: Longitudinal follow up of a multi-centre cohort study (The HAPIEE Project). 07 Nov 2006
In 2002, the Wellcome Trust awarded us a programme grant to establish a large prospective multi-centre cohort study to investigate social, psychosocial, dietary, lifestyle, biological and genetic determinants of the high rates and wide social disparities in cardiovascular diseases and other chronic conditions in Eastern Europe. The cohorts, based in Novosibirsk (Russia), Krakow (Poland), and six Czech towns, are now established. Extensive questionnaire and biological data and biochemical and DNA samples are available on a total of 29,000 men and women 45-69 years old at baseline. Detailed analyses of the baseline data are under way. In addition, at no extra cost to the Wellcome Trust, the cohorts are currently being re-examined and a fourth cohort is being set up in Lithuania. This proposal seeks funding for the crucial longitudinal phase of the study: the mortality and cardiovascular morbidity follow up and the analyses of the longitudinal data. Deaths will be identified through mortality registers; incident non-fatal cardiovascular events will be identified by postal questionnaires and linkages with hospital records and with existing registers of myocardial infarction and stroke, and validated against established criteria. The longitudinal analyses will investigate the relationship between baseline risk factors and fatal and non-fatal events.
Despite the importance of glial cells, our lack of knowledge about their diversity is a major impediment to analyzing their roles in brain function. Here we will address this by: (i) using transgenic techniques to label specific classes of CNS oligodendrocytes and astrocytes in living mice; (ii) studying the labeled oligodendrocytes and astrocytes in live brain slices by electrophysiology and imaging techniques; (iii) using transgenic techniques to disrupt the functions of particular subpop ulations of oligodendrocytes or astrocytes in vivo, and determining the effects on CNS development and function. With this strategy we will investigate the following major questions remaining to be answered about the properties of CNS oligodendrocytes and astrocytes: (a) Do the dorsally- and ventrally-derived subclasses of oligodendrocytes have different electrophysiological properties? (b) Do oligodendrocyte NMDA receptors play a role in controlling myelination? (c) What are the propertie s and function of the NG2-positive putative oligodendrocyte precursor cells? (d) Where are different astrocyte classes generated, and what is their lineage relationship? (e) Do different astrocyte classes have different electrophysiological properties? (f) Do different astrocyte classes have different functions?
Livingstone Online. 14 Nov 2006
The published letters will make available a virtually unknown resource containing detailed medical historical observations of South and Central Africa in the nineteenth century. The letters reveal the role of science and medicine in projected colonial settlement. In addition, since a great number of the letters were written in London (including many to government officials and ministers), they are an invaluable resource for understanding the construction of scientific networks in the metropolis.
Molecular dissection of the CFTR gating cycle, combining mathematical tools with experimental biophysics. 09 Nov 2006
CFTR, whose dysfunction causes the disease cystic fibrosis, belongs to the superfamily of ABC proteins, which couple hydrolytic cycles at conserved nucleotide-binding domains (NBDs) to diverse cellular functions. CFTR is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing (gating) of the ion-permeation pathway is controlled by ATP binding and hydrolysis at its NBDs. But how are conformational signals, originating at the catalytic site, transmi tted to the channel gate? In alignments of homologous sequences one can discern sets of positions at which amino acid distribution has varied in a concerted way. This correlation in evolutionary space likely reflects conservation of a network of energetically coupled residues that mediates transmission of allosteric signals in individual ABC proteins. We will select coevolving positions as targets for mutagenesis and, using new mathematical tools to analyse single channel activity, we will foll ow how the energetic coupling between pairs of side-chains changes during the gating cycle. Together, these studies will compose a molecular description - in both space (within the protein s structure), and time (along the reaction coordinate of CFTR s functional cycle) of the allosteric coupling mechanism that links CFTR s hydrolytic and gating cycles.
Defining genotype/phenotype relationships in known and novel causes of hyperinsulinaemic hypoglycaemia 09 Nov 2006
Hyperinsulinaemic hypoglycaemia (HI) is a clinically and genetically heterogeneous disorder with mutations in five genes reported to date. We have recently found a new cause of transient hypoglycaemia due to mutations in the HNF4A gene encoding the transcription factor HNF-4 . The aim of this project is to characterise this novel cause of hypoglycaemia and to compare with the previously described types of hyperinsulinism. A large cohort (>200) of patients with hyperinsulinaemic hypoglycaemia is already available for this purpose and this resource will be expanded with further recruitment of patients with both severe HI (referred to KH at GOS) and milder, sometimes transient HI (national recruitment programme co-ordinated by JPS in Bristol). Mutations in known genes will be identified by a combination of high throughput sequencing, mRNA analysis and gene dosage studies. New genetic aetiologies will be sought by candidate gene analysis and homozygosity mappingin consanguineous families not linked to known loci. These studies will provide new insights into the physiology of the human beta cell and may have potential treatment implications for both hypoglycaemia and diabetes.
Regulation of Nav1.7 function. 12 Oct 2006
Gene knock-out studies have shown that the voltage-gated sodium channel Nav1.7 plays an essential role in inflammatory pain and noxious mechanosensation. Human heritable inflammatory pain conditions have also been mapped to gain-of-function mutations in Nav1.7. A range of inflammatory mediators (e.g. NGF, carrageenan, formalin) acting through different second messenger systems all require Nav1.7 to alter pain thresholds in the periphery by unknown mechanisms. We will investigate how inflammat ory mediators alter Nav1.7 activity and neuronal excitability in the hope of finding new routes to interfere with Nav1.7 function. To do this we will study epitope-tagged and fluorescent forms of a mutated (TTX-resistant) Nav1.7 expressed in native sensory neurons lacking other TTX-resistant channels. We will investigate the effects of inflammatory mediators on Nav1.7 function and expression using electrophysiological and trafficking assays. The major role of Nav1.7 in noxious mechanosensation suggests that Nav1.7 could be part of macro-molecular complex in nerve terminals that controls pain thresholds. We will identify proteins interacting with Nav1.7 using a yeast-2-hybrid screen employing an excellent DRG-derived yeast library and investigate the role of validated accessory proteins on Nav1.7 trafficking, and function as well as their possible contribution to mechanosensation.
Pyridoxal phosphate (PLP) and epilepsy. 12 Oct 2006
The aim of the project is to develop and apply methods for:-i) determination of the six B6 vitamers and pyridoxic acid in body fluids; ii) determination of the activity of enzymes that affect pyridoxal phosphate homeostasis; iii) sequencing and expression of the corresponding genes; iv) determination of the activity of PLP-dependent enzymes involved in the metabolism of neurotransmitters and neuromodulators and analysis of the corresponding genes. These, and methods already developed, will be u sed to examine 5 hypotheses: a) atypical pyridoxine-dependent seizures can be caused by mutations in the ALDH7A1 gene; b) epilepsy with progressive spastic paraparesis and hyperlysinaemia can be caused by mutations in the U26 gene; c) infants with a CSF profile suggestive of PLP deficiency but no response to PLP therapy have mutations in the pyridoxal kinase gene; d) some patients with seizures and high CSF threonine (but no other signs of PLP deficiency) have mutations in the PLP-dependent seri ne racemase gene. Improved understanding of genetic factors involved in the control of the PLP concentration in brain cells should lead to more rational use of pyridoxine and PLP in epilepsy.
The hydrolysis of PI(4,5)P2 by phospholipase C isoenzymes is a conserved signalling mechanism used by animal cells to regulate a range of core cellular responses such as cell division, differentiation, changes in shape and migration. Despite the widespread use of PI(4,5)P2 as a signalling substrate, its levels in animal cells are stable and demonstrable changes during normal cell signalling are at best minimal. In order to tightly regulate PI(4,5)P2 levels at cellular membranes, it is essential for cells to closely match the rate of PI(4,5)P2 resynthesis to its consumption by PLC activity(Rana and Hokin, 1990; Rhee and Choi, 1992). A major mechanism that contributes to PI(4,5)P2 resynthesis is the sequential phosphorylation of phosphatidylinositol (PI) by PI and PIP kinases. In order for this mechanism to operate optimally, an adequate supply of PI needs to be available at cellular membranes for the sequential phosphorylations required to generate PI(4,5)P2. PI is synthesized in the endoplasmic reticulum (ER) by PI synthase and needs to be transferred from the ER to membranes where PI(4,5)P2 resynthesis occurs. One class of proteins that can perform this function are PITP (Wirtz, 1991). However their ability to transfer PI between membranes in vivo and its contribution to supporting PI(4,5)P2 resynthesis (Cunningham et al., 1995; Hardie et al., 2001; Kauffmann-Zeh et al., 1995) remains unknown. The proposed research will test the requirement of phosphatidylinositol (PI) transfer activity for the in vivo function of PITP in supporting PI(4,5)P2 resynthesis.
Graded hedgehog signalling in the neural tube: mathematical modelling of a developmental multistate switch. 01 Nov 2006
Morphogens are graded positional cues that control cell fate specification in many developing tissues. The activity of Sonic Hedgehog (Shh) in the spinal cord represents an example where progress has been made in understanding morphogen activity. In response to graded Shh signaling, distinct neuronal subtypes emerge in a precise spatial order from progenitor cells arrayed along the dorsoventral axis of the spinal cord. Cross-repressive interactions between responding genes appear to ensure the generation of discrete changes in gene expression. Thus, graded Shh signalling controls a multiway differentiation switch composed of concentration-dependent gene-regulation and a network of interactions between responding genes. Here we propose to analyse this process using a combination of mathematical and developmental biology. The mechanisms by which a gradient of Shh signalling is formed, refined and interpreted are not well understood. We will construct a mathematical model which describes the formation and interpretation of the Shh gradient. In vitro and in vivo experiments in embryos will be used as the foundation of the model and to test key predictions. The resulting model will be used to analyse how graded Shh effects a multiway switch and to identify critical features of the mechanism that confer precise and reliable patterning.
Load theory has resolved the fundamental debate in attention research on the extent to which attention can prevent distraction by irrelevant stimuli and has stimulated much behavioural and neuroimaging research over the last decade. The next challenge is to achieve better understanding of the underlying mechanisms by which load on different brain functions (perception, working memory) affect the ability to focus attention on a task whilst ignoring task-irrelevant stimuli. Specifically, our key g oals are: 1) To establish the effects of the level and type of load on perceptual sensitivity as behaviourally assessed with d prime. 2) To test with functional imaging a neural base-line shift account for the effects of load. 3) To examine the effects of load on visual cortex excitability, as assessed with the intensity of the trasncranial magnetic stimulation needed to trigger phosphene perception. 4) To test the distinction between active versus passive control of attention by load using beh avioural and neuroimaging techniques. The research proposed would provide better understanding of the mechanisms by which focused attention prevents being distracted by goal-irrelevant stimuli as well as clearer conception of the role for executive functions such as working memory in control of focused visual attention.
There is now compelling evidence that the maintenance of pain states is dependent on descending facilitation from the brainstem. This facilitation is in part serotonergic and derived from a subset of neurons located in the rostroventral medulla. Ablation of spinal serotonin attenuates peripheral neuropathic pain states in rats. Our first goal is to establish that the serotonergic pathway is distinct from other descending facilitatory pathways. The second goal is to monitor the dynamics of serot onergic activity in normal and neuropathic rats by measuring i) the evoked and spontaneous activity of superficial dorsal horn projection neurons and ii) the influence of serotonin and serotonin receptor antagonists on projection neuron activity. The third related goal will be to monitor changes in serotonergic tone in the dorsal horn of neuropathic rats using microdialysis. Finally, we will apply this data to our research into the activity of the 5HT pathway in mouse models of pancreatic and bone cancer pain where the regulation of 5HT synthesis in the rostroventral medulla appears to be directly correlated with the appearance of the pain state.
Better understanding of the complex relationships between pregnancy, HIV disease progression and antiretroviral therapy (ART) used to prevent mother-to-child transmission (PMTCT) and/or to delay disease progression is essential to understand the longer term risks of pregnancy for HIV infected women. It is unknown whether a potential synergy between HIV and pregnancy-related immune changes, coupled with an indirect effect of less aggressive therapeutic management in pregnancy, could negatively af fect HIV disease progression in the years following delivery. Women with and without pregnancies since their HIV diagnosis will be compared to quantify the impact of pregnancy on HIV disease progression, through data linkage between the UK National Study on HIV in Pregnancy and Childbirth and the UK Collaborative HIV Cohort Study. An individual patient data meta-analysis of data from this and other European cohorts will be performed. A new prospective cohort study of Ukrainian HIV-infected wom en, recruited postnatally but identified antenatally/intrapartum will be established to estimate the impact of exposure to abbreviated antenatal ART for PMTCT, treatment and co-infection on the course of HIV infection and prognostic markers of HIV disease progression in this resource-poor setting. Results will guide the treatment and management of HIV-infected women during and after pregnancy.
Cluster randomised controlled trial of the effect of community mobilisation onneonatal survival in Mumbai slums. 05 Dec 2006
Goal: To improve the survival and health of mothers and newborn infants in slum communities in Mumbai, India. Purpose To test an intervention that mobilises communities for better health care, in which local women's groups build an understanding of their potential to improve maternal and infant health and develop and implement strategies to do so. Design A cluster-randomised controlled trial of community mobilisation to achieve improvements in pregnancy, delivery, postpartum and neonatal care. The participatory action research intervention will be introduced in vulnerable areas of slums in six wards of Mumbai. After random allocation of 48 clusters to either intervention or control groups, indicators of effect will be measured through a vital surveillance system implemented by the project. Key distal outcome indicators will be neonatal mortality and maternal and neonatal morbidity. Key proximate outcome indicators will be home care practices, uptake of antenatal, delivery and postnatal care, and care for maternal and neonatal illness.
A Bayesian account of the mirror system. 13 Dec 2006
Social interaction depends upon our ability to infer beliefs and intentions inother minds. Impairments of this ability can lead to major developmental and psychiatric disorders such as autism and schizophrenia. Little is known about the neural basis of our ability to read' the intentions of others, but a very likely candidate is the mirror neuron system.These neurons discharge, not only when an animal model acts, but also when the animal observes someone else performing the same action. However, it is not known how someone else's intentions can be inferred by the mirror system. The proposed research addresses this issue. More specifically I propose that the mirror system is best considered within a predictive coding framework that appeals to empirical Bayes. Within this scheme the most likely cause of an observed action can be inferred by minimising the prediction error at all levels of a cortical hierarchy that is engaged during action observation. This account specifies a precise role for the mirror system in our ability to infer intentions and formalises the underlying computations. Furthermore, it makes specific predictions about the behaviour and organisation of the mirror systemthat can be tested empirically. The proposed research will test these predictions.
The role of TIMP3 and TIMP3 polymorphisms in the inflammatory and fibrotic events observed in interstitial lung disease. 07 Dec 2006
Pulmonary fibrosis represents the end stage of a heterogeneous group of interstitial lung diseases (ILD) with poor prognosis and no effective treatment. The pathogenesis of ILD is incompletely understood however, a marked change in the normal balance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) occurs. The host centre has reported that TIMP3 polymorphisms appear protective against susceptibility to pigeon breeders' disease. I also have data suggesting they influence susceptibility to sarcoidosis. TIMP3 may play key roles in the regulation of inflammation, apoptosis and fibroproliferation. However, the relative importance of TIMP3 in the various stages of ILD and therole of TIMP3 polymorphisms is unknown. I hypothesise that TIMP3 contributes to the pathogenesis of ILDs through effects on inflammatory and fibrotic processes and that functional polymorphisms in the TIMP3 gene will influence these processes. To address this hypothesis I will identify and determine the function of TIMP3 polymorphisms relevant to ILD. I will also examine the effect of TIMP3 deficiency on lung injury and fibrosis in an animal model of lung fibrogenesis. These studies will provide fundamental information on the role of TIMP3 in ILD. It may enable subjects 'at risk of disease to be identified and ultimately lead to new targets for intervention.