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Recipients:
University College London
University of Cambridge

Results

The role of Sox2/SOX2 in hypothalamo-pituitary development. 08 Oct 2008

The overall aim of this project is to understand better the role of the transcription factor SOX2 in normal hypothalamo-pituitary development and in the pathogenesis of hypopituitarism in humans. Recently, we have identified a critical role for the transcription factor SOX2 in normal hypothalamo-pituitary development in both mice and humans; however, the molecular mechanism by which SOX2 dictates hypothalamo-pituitary development, namely its target genes and partner proteins, remains unknown. Th e main aims of the proposed research are: 1. To evaluate the ability of SOX2 to directly regulate specific genes known to be involved in forebrain and hypothalamo-pituitary development, and to identify the positions of these genes in the genetic hierarchy leading to normal pituitary development. 2. Identification of novel SOX2 target genes likely to be important in hypothalamo-pituitary development. 3. To investigate suitable co-operative partner factors for SOX2 in the developing pitu itary and their co-expression in human embryos. 4. Selection of candidates for mutation analysis of novel SOX2 target genes in patients with hypopituitarism and associated defects.

Amount: £359,039
Funder: The Wellcome Trust
Recipient: University College London

Endoglin regulates angiogenesis: an investigation of cellular and molecular mechanisms. 10 Nov 2008

Development and maintenance of an optimally functioning vasculature are essential for health. Abnormal vessel responses can result in a range of vascular problems including haemorrhage, vessel dilatation or aneurysm, which may be associated with increased morbidity and mortality, depending on the affected organ. The aim of this project is to understand the role of the essential endothelial receptor endoglin during development of the vasculature. Pathological mutations of the endoglin gene in the familial vascular disorder Hereditary Haemorrhagic Telangiectasia lead to the local formation of arteriovenous malformations and haemorrhagic, dilated and tortuous blood vessels (telangiectases) that often enlarge or become more numerous with age. The molecular mechanisms underlying these events are poorly understood, largely because of a lack of robust animal models. We have recently derived an inducible endoglin knockout mouse which, for the first time, develops arteriovenous malformations in a reproducible manner. We will use this unique model to investigate the underlying cellular and molecular mechanisms responsible for abnormal vascular remodelling. Following this, we aim to investigate repair of these vascular abnormalities. Increased understanding of the central role of endoglin in angiogenesis has wider implications for current therapies to regulate angiogenesis and vascular repair in an extensive range of pathologies.

Amount: £105,970
Funder: The Wellcome Trust
Recipient: University College London

An examination into pathways utilized by Herpes Simplex Virus to establish latent infection. 02 Oct 2008

This application seeks to investigate pathways into latency by Herpes simplex virus Type-1 and to determine the biological consequences of limited gene expression that may occur prior to the establishment of latency. Although it I widely assumed that latency by HSV-1 is a consequence of a block in immediate early gene expression, our recent studies utilizing reporter mice has provided evidence of ICP0 promoter activity in a proportion of neurones during the establishment of latency. We now wish to extend these initial studies to determine (a) the extent of lytic cycle promoter activity that can occur prior to latency establishment (b) analyse marked populations of latently infected neurones for reactivation propensity and latent DNA copy number (c) utilize reporter mice to re-examine the latency phenotypes of mutants lacking latency associated transcripts and ICP0 gene functions. The proposal seeks to investigate novel and previously unrecognized pathways by which HSV-1 can establish latency and develop a quantitative model system by which to investigate latency in marked neuronal subsets.

Amount: £431,409
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of KIR and HLA-C in reproductive success. 02 Oct 2008

Our aim is to unravel the complexities underlying our previous finding that particular maternal KIR with fetal HLA-C combinations (in essence KIR AA and fetal C2) are associated with pre-eclampsia. Successful pregnancy and fetal growth depends on trophoblast infiltration into the uterus and this is most severely deficient in women who have pre-eclampsia and the baby also has FGR. We have access to 100,000 Norwegian samples and can select adequate numbers of these severely abnormal pregnancies to compare with normal controls. We will determine individual KIR gene frequencies and type HLA-C alleles on mother and baby. For the first time we will address how the mother s HLA-C status affects the response of uNK to the fetal trophoblast. We will also focus on one particular KIR, KIR2DL1 and address how polymorphism of this gene encoding the receptor for HLA-C2 alleles influences pregnancy outcome and uNK function. Finally, we aim to translate the genetic studies into functional outcomes usi ng primary uterine NK cells and normal trophoblast. These studies will reveal how the complex system of interacting maternal KIR receptors and fetal HLA-C ligands are critical determinants of clinical outcomes during pregnancy.

Amount: £442,655
Funder: The Wellcome Trust
Recipient: University of Cambridge

Replication for blood cell indicies associations. 18 Feb 2009

We propose a pilot study to test the association of 100,000 specific polymorphisms with a range of common diseases using a two stage case-control study design. The study will include diabetes, breast cancer, cardiovascular disease, bipolar disorder, and other diseases (2,000 samples each), as well as two common control groups (up to 3,000 samples total) for further evaluation. Positive associations will form the basis for future biological studies. The results will be used to evaluate how best to optimise the design, implementation, analysis and cost efficiency of large-scale and genome-wide association studies in the future. We will examine features such as SNP selection, analysis methods, population structure, study size, the use of common controls, heterogeneity in sample collections, linkage disequilibrium and SNP tagging. The results will provide independent assessment of the coverage of SNP panels that are available to the community for genetic studies, including the output of the International HapMap Project. The project will help to establish a separate training programme in statistical genetics, and will lay the foundations for the development of an infrastructure for UK research in this area in future years.

Amount: £29,568
Funder: The Wellcome Trust
Recipient: University of Cambridge

Deciphering mammalian MST/hMOB1/NDR/LATS tumour suppressor networks. 23 Jun 2009

The main objective of my research is to determine how deregulated MST/hMOB/LATS/NDR signalling (also termed mammalian Hippo signalling) contributes to cellular transformation. The main aim is to delineate the key molecular events in mammalian Hippo networks essential for tumour suppression. To achieve this goal I propose the following specific aims: Project 1: Define the molecular role(s) of mammalian NDR1/2 kinases in centrosome biology, the cell cycle and cellular transformation. Project 2: Determine the precise function(s) of LATS2 kinase in cell cycle progression and EMT relating to cancer development. The objective is to decipher mammalian Hippo signalling by selectively manipulating kinase activities or by disrupting specific complexes. To achieve these goals, I will employ an interdisciplinary approach that combines biochemical, molecular and cell biological methods, thereby allowing controlled overexpression, inactivation and depletion/loss of our proteins of choice (p lease see the detailed research plan for details). The precise characterisation of MST/hMOB/LATS/NDR tumour suppressor networks has also the potential to open novel avenues in the pursuit of compounds for cancer treatment. Understanding where, how and why mammalian Hippo signalling is required for tumour suppression will also establish how far NDR/LATS pathway members are suitable therapeutic biomarkers in the fight against human diseases.

Amount: £838,863
Funder: The Wellcome Trust
Recipient: University College London

Systematic Bioinformatic Discovery of 'Hidden' Virus Genes. 23 Jun 2009

This proposal concerns the bioinformatic discovery of genes that have been persistently overlooked in important RNA viruses. Typically such genes are short, overlapping, and/or translated via non-canonical mechanisms. Using my own software packages developed for finding (a) short overlapping genes, and (b) phylogenetically conserved signals for ribosomal frameshifting, I recently identified a number of new virus genes, most significantly short overlapping genes in both the potyviruses and the alphaviruses, both apparently translated as frameshift fusion proteins (Chung et al 2008, Firth et al 2008e). The goal of the proposed research is to create a much larger alignment database by using all relevant RNA virus sequences in GenBank; analyze the alignments using a variety of techniques to systematically identify new 'hidden' genes; and develop additional software packages for virus genome analysis. In addition, I will develop public web-interfaces to key programs and databases develo ped during the fellowship, and extend certain analyses to DNA viruses. A selection of bioinformatic predictions will be experimentally tested in order to establish confidence in the prediction algorithms, stimulate further experimental follow-up by other virologists, and to characterize new stimulatory signals associated with non-canonical translation mechanisms as input for further bioinformatic searches.

Amount: £550,205
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional analysis of Lrig1 and Lrig3 in adult epidermal stem cell self-renewal. 23 Jun 2009

My studies of Lrig1, a negative regulator of receptor tyrosine kinases, have demonstrated a link between stem cell self-renewal and receptor activity. I will establish whether the effect of Lrig1 on stem cell behaviour is a general feature of receptor activation and Lrig family members. Lrig3 will be assessed for its role in vivo in epidermal homeostasis and the effect of receptor tyrosine kinase inhibition and activation will be investigated in vitro. Regulation of receptor kinase activity is e ssential for homeostasis and these aims will help us understand disease progression. I have demonstrated that Lrig1 defines murine interfollicular epidermal stem cells. I will use expression profiling to define the unique properties of Lrig1 expressing cells and perform lineage analysis to establish their role in homeostasis and repair. This will require the generation of a Lrig1::dsRed-IRES-CreERT2 reporter mouse. My studies demonstrate that Lrig1 governs stem cell quiescence. To address whe ther hyperplasia in Lrig1 KO mice is caused by increased stem cell contribution, I will perform in vivo clone assays. The combination of these aims will define the role of Lrig1 and interfollicular epidermal stem cells. This will provide a unique tool to understand how these cells participate in epidermal disorders.

Amount: £970,388
Funder: The Wellcome Trust
Recipient: University of Cambridge

The fusion of optical and magnetic resonance spectroscopy technologies to deliver novel multimodal methods to investigate brain injury in adults and neonates. 23 Jun 2009

The aim of this fellowship is to combine two techniques currently being used to monitor brain injury in adults and neonates; near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS). I will start by developing a novel magnet compatible hybrid optical topography spectrometer (HOTS) that is a combination of broadband and frequency domain spectrometers. HOTS will give regional measurements (2-Dimensional images) of brain tissue total haemoglobin, haemoglobin oxygen saturation, re dox state of cytochrome-c-oxidase, water content, temperature and scattering properties. I will then fuse the HOTS with MRS at an instrumentation level (combining the fibre optics head holder with the MR head coil) and on a software level (image co-registration). MRS scanning provides anatomical information with high spatial resolution measurements of lactate, creatine, phosphocreatine and tissue temperature. The merging of HOTS and MRS can therefore provide complementary physiological informati on. I will test the combined technologies using tissue mimicking phantoms, before a range of in-vivo studies are carried out in adult and neonatal humans and piglets (neonatal animal model). I will then fuse the multimodality data from these studies using systems biology approach utilising a computational model of brain tissue physiology, allowing the translation of the signals from physiological data to clinical information.

Amount: £528,536
Funder: The Wellcome Trust
Recipient: University College London

Building and shaping the central nervous system in higher vertebrates: an integrative approach. 23 Jun 2009

In spite of its fundamental and medical significance, the morphogenesis of the early central nervous system of the amniote embryo remains poorly understood. I propose an integrated study of amniote neurulation as a dynamic process, which is now possible in the chick embryo. Using multi-photon, high-resolution imaging in intact embryos (Nature 449: 1049) and precisely controlled gene targeting methods (Nat Protoc 3: 410) I have recently developed, we will first analyse the global flow of ce ll movements and characterise individual cell behaviours underlying morphogenesis of the early neural tissue. This will allow formulating precise hypotheses on the determinants in this process (cell movements and cell growth), which will be tested functionally. The data from these reductionist approaches will be incorporated into a computer model of the early neurula to understand the shaping of the whole tissue and embryo. In parallel, we will study the naturally occurring stem cells that b uild the main embryonic axis, including the posterior neural plate and axial structures. High-resolution imaging and other direct methods will be used to determine their mode of renewal and the lineage relationships, and we will undertake the molecular characterisation of these cells to study their establishment and differentiation.

Amount: £763,652
Funder: The Wellcome Trust
Recipient: University of Cambridge

Population coding of natural sounds in the mammalian auditory system. 09 Dec 2008

Despite the recent advances in our understanding of sensory function, the neural representation of complex natural stimuli remains a mystery. This gap in our understanding can be attributed to two complex properties of sensory systems that are important under natural conditions, but are not addressed in typical laboratory experiments involving recordings of the responses of a single neuron to simple stimuli: (1) the response properties of sensory neurons are not static, but are constantly adapte d to match the current statistical properties of the stimulus and (2) the representation of complex stimuli is not confined to the response of a single neuron, but is distributed across the responses of an interconnected population. I plan to study these complex properties in the inferior colliculus (IC) of the auditory midbrain. I will record the responses of small populations of neurons simultaneously during the presentation of natural stimuli and characterize the response properties of these neurons using a variety of system identification and information theoretic techniques. I will also use these experimental results to develop a model that incorporates the effects of adaptation and population interconnectivity in predicting neural responses to natural sounds.

Amount: £691,979
Funder: The Wellcome Trust
Recipient: University College London

Investigation of the nuclear reprogramming process using defined factors. 09 Dec 2008

Understanding the biology of nuclear reprogramming, which is the conversion of adult cells back into an embryonic stem cell state, is a fundamental question in biology with huge potential for regenerative medicine. Recent advances in the field have started to identify genes that instruct this genome plasticity. I previously identified Nanog as a limiting factor for the conversion of Neural Stem (NS) cells to pluripotency after cell fusion to Embryonic Stem (ES) cells(1). Subsequently, induction of mouse embryonic fibroblasts to a pluripotent stem (iPS) cell state was achieved by expression of four factors, cMyc, Oct4, Klf4 and Sox2, after retroviral infection (2, 3). Despite recent advances, much is still unknown regarding the basic biology of nuclear reprogramming. After the landmark discovery of iPS cells and building from my previous work on cell fusion I have developed a system whereby somatic cells are reprogrammed rapidly and efficiently to full pluripotency by chemical inhibitio n (7). To follow up on this work I outlined a plan of research aiming to: (i) elucidate the mechanisms of the nuclear reprogramming process (ii) identify the network of factors orchestrating nuclear reprogramming (iii) evaluate the nature and the developmental potential of iPS cell precursors.

Amount: £768,414
Funder: The Wellcome Trust
Recipient: University of Cambridge

A machine learning approach to the analysis of psychiatric neuroimaging data. 09 Dec 2008

The World Health Organization (WHO) states that one in four people experience a mental health problem during their life. The development of technologies for assisting psychiatric diagnosis and predicting treatment responses is extremely relevant to avoid inefficient treatment and to promote mental health. The purpose of this research is to develop models and tools for the application of novel machine learning techniques to the analysis of brain scan data to assist in the understanding, diagnosis and prognosis of psychiatric disorders. Key Goals: 1. Development of new machine learning techniques for the analysis of brain scans including: - Probabilistic classifiers to predict group membership (e.g. patients vs. controls and - responders vs. non-responders); - Hypothesis-driven models of brain alterations in psychiatric disorders (e.g. schizophrenia, depression); - New strategies to extract useful information from neuroimaging data (i.e. feature selection approaches). 2. Developme nt of multi-modal classification integrating data from different techniques (e.g. fMRI, MRI, EEG, genetic data). 3. Validation of the developed approaches using a variety of data sets. 4. Translation of the validated approaches into clinical practice, i.e. development of a toolbox that could be used for aid diagnosis of psychiatric disorders and other clinical/outcome goals.

Amount: £619,620
Funder: The Wellcome Trust
Recipient: University College London

A new player in MHC class I processing and presentation. 09 Dec 2008

Peptide loading of Major Histocompatibility Complex (MHC) class I molecules is essential for their function in the immune system. I have recently identified a novel molecule, named TAPBPR, can inhibit this process. In cells expressing TAPBPR, the expression of conventionally folded MHC class I heterotrimers is decreased. In their place, unconventional forms of MHC class I molecules are displayed. Such alterations to MHC class I surface expression is likely to have a significant impact on immu nological recognition and consequential influences on immune responses. Thus, it is essential to further understand the role of this novel molecule, TAPBPR, in the context of human Immunology. This project aims to elucidate the immunological function of TAPBPR in MHC class I processing and presentation. Two key areas in which TAPBPR expression, and its consequential affects on MHC class I expression, will be explored: 1) The role of TAPBPR in cellular stress 2) The role of TAPBPR in cro ss-presentation in Dendritic cells Ultimately, this project aims to elucidate the role of TAPBPR and its contribution to human health and disease.

Amount: £493,514
Funder: The Wellcome Trust
Recipient: University of Cambridge

Reading and writing the prolongation of life. 26 Mar 2009

This research examines the role of writing in seventeenth-century works on the prolongation of life. It examines the relationship between knowledge and the extension of experience presented by authors, and situates such projects within a wider natural philosophical endeavour to use artifice to overcome man s natural limitations. It proposes that what appear to be practical schemes for prolonging life are in fact about the feat of longevity that is made possible only by the artifice of writing. This research will offer a new understanding of the relationship between natural philosophy and medicine by providing a new reading of these works. It will show that these works conceive knowledge and long life to be fundamentally connected, and reads them as an intervention in contemporary debates about progress. These authors present prodigious old age as a feature of the experience accumulated in the library, rather than chronological precedence. In doing so, they make literary and i ntellectual endeavour rather than the arts the site of progress through experience. The key goal of this research is a monograph on feats of the library, bringing together my thesis research on extending experience through space with the proposed research on extending experience through time.

Amount: £112,995
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Rise of the Surgeon in Restoration London: Richard Wiseman and his Contemporaries. 26 Mar 2009

In 1937, Fenwick Beekman argued that most surgical advancements took place in Scotland during the early Enlightenment. Consequently, historians focused heavily on institutional histories of surgery in Glasgow and Edinburgh. More recently, however, Phillip Wilson redirected that focus when he charged historians with neglecting London s surgeons and their practices in his own biographical study of Daniel Turner. Wilson was right in redirecting our attention. After the Restoration, surgeons bec ame a more public and powerful group in London. Their numbers increased; they published more; and they partook in the important debate between learned and new medicine. Put simply, surgeons had become a formidable force by the end of the seventeenth century. My project proposes to investigate the causes behind this change and provide a deeper understanding of how surgeons interacted with each other, their patients and other types of medical practitioners during this period. It does this by c ombining a study of several notable surgeons with other kinds of institutional and social histories. This in turn will demonstrate the ways in which surgeons laid claims to medical expertise and how they used those claims to elevate their social, political and intellectual status after the Restoration.

Amount: £133,992
Funder: The Wellcome Trust
Recipient: University College London

What's in a name? Authorship and authority in the transmission of medicinal recipes from Hippocrates to Galen 29 May 2009

Names (real authorial names or pseudonyms) attached to ancient pharmacological treatises, or within a treatise, to individual recipes, conferred authority on pharmacological material. This project will investigate the relation between authorship and authority in the transmission of pharmacological knowledge in antiquity, taking into account variations through time, variations according to the literary genres in which recipes are listed, and variations according to the social origin of the authority named. I will study Greek and Latin sources from the second half of the fifth century BC (approximate date of the recipes preserved in the Hippocratic Corpus) to the end of the second /beginning of the third century AD (date of the pharmaceutical treatises in the Galenic Corpus). I will write five chapters covering the strategies used by pharmacological compilers to establish their authority; the methods of source quotations in pharmacological writings; the involvement, real or imagined, of political figures in pharmacology; the appropriation of traditional remedies by medical writers; and parallel versions of recipes attributed to individuals. Building upon my previous research on pharmacological recipes, and drawing upon recent studies on the history of the book, this study will enhance our understanding of the construction and transmission of ancient medical knowledge.

Amount: £11,167
Funder: The Wellcome Trust
Recipient: University of Cambridge

An investigation into a viral cause of chronic hepatitis. 09 Jul 2009

Chronic hepatitis (CH) in canines is frequently diagnosed and usually idiopathic although histological and clinical features are classical for a viral aetiology. Breed predilections indicate a genetic predisposition to disease, and some breeds show a particularly severe form of CH. CH in humans has multiple defined aetiologies (most commonly viral). Some idiopathic cases remain for which one or more novel viral agents are suspected. Histopathological lesions between a subset of these human cases an d idiopathic canine CH are strikingly similar. Hypothesising that canine CH is of viral aetiology, the key goals of the project are: 1. To identify a virus causing CH. 2. Investigate the MHC haplotypes. I will use state of the art PCR and high-throughput sequencing techniques to identify viruses present in severely affected tissues. Using serological techniques and specific PCR assays I will determine the correlation of infection and disease. Pedigree analysis and MHC haplotyping will be used to investigate the genetic correlates of disease susceptibility and severity.

Amount: £204,126
Funder: The Wellcome Trust
Recipient: University of Cambridge

Does increased household income among the poor contribute to reversal of the social gradient of obesity in Egypt? 10 Jun 2009

The global obesity epidemic is spreading rapidly in developing countries with a social distribution that varies according to level of economic development. In urban Egypt, obesity appears to have become more common among poor women compared to the rich which is the reverse of the expected social distribution of obesity at Egypt s stage of economic development. Observational data suggest that increases in income have a particularly detrimental effect on dietary quality of the poor, which could explain why economic development puts the poor at particularly high risk. This proposal aims to test the hypothesis that increased income increases obesity risk among poor women in Egypt through its effect on consumption of energy-dense foods. A multi-pronged approach will be used: cross-sectional analysis of a Cairo population survey using multivariable regression and multilevel modelling; and a community based experimental study evaluating the impact of conditional cash transfer on dieta ry intake and obesity among rural poor women. It is expected that the study will i)provide the applicant with high-quality training in research methods for the investigation of complex health problems such as obesity; ii)make significant contributions to the evidence base informing national, regional and global health-related policy; and iii)strengthen South-North research networks.

Amount: £180,817
Funder: The Wellcome Trust
Recipient: University College London