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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
Amounts:
£500 - £1,000
£100,000 - £500,000

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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

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

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

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

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

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

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

The impact of HIV and antiretroviral therapy on the cardiovascular system in HIV-infected children. 10 Jun 2009

HIV and some antiretroviral (ARV) drugs are associated with impaired cardiac and vascular function in adults, but little is known about the impact in HIV-infected children. This project will explore the relationships between HIV infection, immune activation and cardiovascular phenotype in HIV infected children living in Africa recruited to a funded pharmacokinetic study of different nucleoside reverse transcriptase inhibitors CHAPAS 3. I will make serial measurements of Carotid Intimal Media l Thickness (CIMT) and Pulse Wave Velocity (PWV) over 96 weeks in 2 HIV infected cohorts (1 70 children stable for more than 2 years on ARVs and 2 70 children about to start ARVs). Findings will be compared to HIV negative matched community controls (n=140). The primary outcome measure of my project will be differences in PWV between the 3 groups at 96 weeks. Additional measurements of vascular injury (circulating endothelial cells, endothelial microparticles and soluble vascular adhesi on molecules) and markers of immune activation (D-Dimer, Interleukin-6, high sensitivity CRP) and lipid profiles will also be made. Alongside factors such as cost, the results are likely to influence future guidelines and policy decisions on first line antiretroviral therapy in HIV-infected children worldwide.

Amount: £371,694
Funder: The Wellcome Trust
Recipient: University College London

Investigation of the genetics and the phenomenon of spontaneous involution of giant Congenital Melanocytic Naevi. 09 Jul 2009

2 inter-related research projects are proposed: o Investigation of the genetics of Congenital Melanocytic Naevi (CMNs) o Investigation of spontaneous lightening of CMNs Giant CMNs are extensive developmental abnormalities of the neural crest about which little is known. 20% of patients have abnormalities of the CNS as well as the skin. Identification of the genes involved in the development of CMNs would contribute to knowledge of neural crest cell development. We propose to use skin biopsy material of affected and unaffected skin, as well as blood samples, to try to identify candidate gene regions involved in the aetiology of giant CMNs. Quantification and investigation of the phenomenon of spontaneous involution seen in certain cases could contribute to knowledge of the behaviour of normal melanocytes and may allow exploitation of the mechanism for the treatment of future patients. We propose to quantify colour change over a two year period and compare it with the his tological findings of the skin biopsies and the blood markers, as well as with any genetic findings. Key goals are o identification of involved loci in either germline or somatic DNA o quantification of spontaneous lightening and the classification of this phenomenon into either immunological or apoptotic.

Amount: £228,823
Funder: The Wellcome Trust
Recipient: University College London

Exploring the impact of vertically acquired HIV infection on the quality of humoral immunity in early adulthood . 09 Jul 2009

Perinatally-acquired HIV infection is a global concern, yet little is known about how HIV affects immune system development and whether timely use of ART is critical to minimise lasting HIV-mediated damage. Although T cells are the primary target of HIV, significant disruption to humoral immunity is described in horizontally infected adults. Some changes are reversed on control of viral load/recovery of CD4+ count with ART; however the generation and maintenance of long lived memory B cell respo nses remain impaired. Availability of an increasing cohort of vertically infected young adults provides me with the opportunity to study, for the first time, the impact of perinatally-acquired HIV infection on the development of adaptive immunity and how these patients differ immunologically from adults who acquired infection in the context of a mature immune system and from healthy controls. A comprehensive analysis of B cell lineage development, turnover and the quality of natural immun ity to the colonising bacteria pneumococcus, will be made in a cross sectional study incorporating the three patient cohorts. Subjects will then be immunised with pneumococcal vaccine and the quality and persistence of memory responses analysed. This information will be used ultimately to inform clinical management of perinatally infected patients.

Amount: £240,331
Funder: The Wellcome Trust
Recipient: University College London

Dopaminergic neuromodulation of memory and behaviour: implications in aging. 09 Jul 2009

Structural and functional MRI (fMRI) has demonstrated that age-related memory decline is characterized by changes in medial temporal lobe and prefrontal structures. Recently it has been recognized that molecular mechanisms involving specific neurotransmitters, such as dopamine, are also affected in aging. Dopamine is released by neurons in the substantia nigra/ventral tegmental area (SN/VTA) of the midbrain and plays a critical role in the long-term consolidation of memories in the medial tempor al lobes. However, to date there is little quantitative in vivo data available on how structural parameters of the SN/VTA and dopamine neuromodulation relate to memory performance in older adults, and to consolidation in particular. I wish to test a hypothesis that decrements in dopaminergic neurotransmission have a quantitative relationship to impaired memory consolidation, reward-related enhancement of memory and altered reward-based choice behavior in aging. To achieve this I will study 30 healthy elderly subjects who will undergo clinical and behavioural assessment, high resolution structural MRI and fMRI using a memory consolidation and reward learning task paradigm. I will combine these measures with pharmacological manipulation of dopaminergic neurotransmission. This integrative approach will allow bridging of clinical phenotypes and structural/functional imaging and pharmacology, to further characterise age-related cognitive and behavioural impairments.

Amount: £156,095
Funder: The Wellcome Trust
Recipient: University College London

The molecular and functional characterisation of dimethylarginine dimethylaminohydrolase in acute-on-chronic liver failure, and determination of its role in portal hypertension 01 Apr 2009

The pathobiology of portal hypertension in response to liver injury in acute-on-chronic liver failure (ACLF) is yet to be determined. Recent work has demonstrated an association of liver inflammation and abnormalities in the metabolism of asymmetric dimethylarginine (ADMA) with portal hypertension and prognosis in ACLF. We hypothesise that altered ADMA metabolism in response to liver inflammation may propagate liver injury and portal hypertension in ACLF. This project will explore th e effect of manipulation of ADMA metabolism in determining the response to liver injury in rodent models of cirrhosis. Genetic and pharmacological manipulation of dimethylarginine dimethylaminohydrolase (DDAH), the major enzymatic route of ADMA elimination, will be used to modulate the degree of liver injury in response to bacterial lipopolysaccharide administration. The key aims of the project are: 1. To characterise the effects of superadded inflammation on DDAH gene expression, protein expression, cellular localisation and activity, and on portal haemodynamics, in cirrhosis. 2. To determine the molecular effects and changes in hepatic haemodynamics following pharmacological interventions that modulate inflammation, oxidative stress and DDAH-1 expression, in cirrhosis. 3. To determine whether DDAH-1 over-expression confers protection against increased liver injury and mortality following superadded liver inflammation in cirrhosis.

Amount: £185,766
Funder: The Wellcome Trust
Recipient: University College London

Control of Attention in the human brain studied with real-time fMRI. 04 Dec 2008

Many forms of brain damage, either acute or progressive, can compromise patients ability to move and to communicate. While much work has focused on attempts to reverse the pathological process causing such damage, rather less has sought to provide complementary approaches of circumventing the effects of damage by using brain signals from sensory or motor cortex to control neuroprosthetic devices. Moreover, investigating the neural basis of such signals has direct biological relevance for unders tanding mechanisms of perception and action. Here, I propose to use the new technique of real-time fMRI (rt-fMRI) to address both issues. My proposal thus addresses two inter-related questions of biological and practical significance. First, can attention be decoded in real time from human visual cortex to potentially provide control signals for a neural prosthesis? Second, does the level of attentionally modulated activity in human visual cortex have a causal influence on perception and awarene ss? I will combine real-time functional MRI (rt-fMRI) with on-line neurofeedback in human participants in a series of experiments that both probe the effects of attention on visual cortex and evaluate the potential utility of decoding such signals for communication and control.

Amount: £189,768
Funder: The Wellcome Trust
Recipient: University College London

Cone photoreceptor rescue in inherited retinal degenerations. 04 Dec 2008

This project is to investigate whether slowing cone photoreceptor loss could be used as a widely applicable treatment to preserve sight in inherited retinal degenerations. Neurotrophic factors, apoptosis inhibitors and transplanted rods have previously shown promise, but key questions remain: 1. Are initial rescue effects maintained over time, or subsequently lost by accelerated apoptosis? 2. Can cone cell rescue still be achieved once all rods have degenerated (a common clinical scenario)? 3. Could rods transplanted into the vitreous slow cone degeneration (the vitreous is a clinically attractive site for cell transplantation)? These questions will be addressed using adeno-associated viral (AAV) gene transfer to achieve sustained intraocular levels of a promising neurotrophic factor with a clinical safety profile (GDNF - delivered to inner retinal cells by AAV serotype 2) and cone selective expression of a potent intracellular inhibitor of apoptosis (XIAP - delivered to photo receptors by AAV serotype 5). In the third experiment rod progenitors will be isolated and transplanted into the vitreous cavity. All experiments will be performed in a novel mouse model of rod-cone degeneration in which the cones are genetically labelled with a fluorescent probe, allowing repeated anatomical and functional tracking of the degeneration over time.

Amount: £179,898
Funder: The Wellcome Trust
Recipient: University College London

Transthyretin depletion for treatment of hereditary systemic and senile cardiac amyloidosis 29 May 2009

Systemic transthyretin amyloidosis is a fatal late onset disease caused by tissue deposition of amyloid fibrils composed of variant and wild type transthyretin. The objective of the project is to construct compounds to trigger the accelerated clearance of plasma transthyretin molecules by the liver by synthesising palindromic ligand-linker-ligand compounds capable of cross-linking transthyretin molecules or oligosaccharide-ligand conjugates that direct hepatic clearance, which could be used as drugs for treating and preventing acquired and hereditary human systemic transthyretin amyloidosis. The aim is to optimise the design, synthesis, and properties of a transthyretin depleting drug and complete the comprehensive safety and efficacy evaluation required prior to administration of a validated candidate compound in humans.

Amount: £97,674
Funder: The Wellcome Trust
Recipient: University College London

Transthyretin depletion for treatment of hereditary systemic and senile cardiac amyloidosis 19 Dec 2008

Systemic transthyretin amyloidosis is a fatal late onset disease caused by tissue deposition of amyloid fibrils composed of variant and wild type transthyretin. The objective of the project is to construct compounds to trigger the accelerated clearance of plasma transthyretin molecules by the liver by synthesising palindromic ligand-linker-ligand compounds capable of cross-linking transthyretin molecules or oligosaccharide-ligand conjugates that direct hepatic clearance, which could be used as drugs for treating and preventing acquired and hereditary human systemic transthyretin amyloidosis. The aim is to optmise the design, synthesis, and properties of a transthyretin depleting drug and complete the comprehensive safety and efficacy evaluation required prior to administration of a validated candidate compound in humans.

Amount: £610,617
Funder: The Wellcome Trust
Recipient: University College London

Novel resolution-phase macrophages restore post-inflammation tissue homeostasis 06 Apr 2009

While the objective of acute inflammatory resolution is for cell clearance and pro-inflammatory mediator catabolism, tissues must undergo a final process of restoration of tissue homeostasis. This is not only essential for immune recovery but it restores physiology and prepares tissues to mount appropriately-tempered inflammatory responses to future infections or injuries. On this theme, I identified a new population of macrophages found at sites of resolving inflammation that play a central rol e in this process, called resolution-phase (rM) cells. Through the release of unknown prostanoids and/or chemokines, rM trigger the repopulation of innate-type lymphocytes (rLYM), which are crucial for controlling acute inflammatory responses to subsequent infection/injury and curtailing mortality. Therefore, this application proposes to indentify the rM-derived signals that trigger lymphocyte repopulation and elucidate the lymphocyte subpopulation/s responsible for post-resolution protection. A lso, with access to human resolving inflammatory samples I will investigate whether signaling pathways that restore homeostasis in mice also occur in humans. Thus, I believe that tissues revert back to homeostasis after injury/infection in an active manner controlled by soluble mediators and cellular players inherent to pro-resolution processes. By uncovering these novel pro-homeostatic pathways I hope to advance our understanding of chronic inflammatory diseases and susceptibility to infection.

Amount: £1,481,973
Funder: The Wellcome Trust
Recipient: University College London