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Funders:
The Wellcome Trust
Recipients:
University College London

Results

Mentalizing and social conformity: Pharmacological manipulations and underlying mechanisms. 12 Jul 2011

The proposed research project focuses on the neurobiology of social behaviour.Neuroimaging experiments will be combined with pharmacological manipulations to better understand the mechanisms and computations underlying social information processing. We recently developed a paradigm to modulate participant's preferences in an intertemporal choice task (Garvert et al., in preparation). This paradigm is apotentially powerful tool for conceptualizing and quantifying the implicit effects mentalizing exerts on decision making. l aim to use this task to studythe biological mechanisms underlying behaviour of individuals placed in socialsituations by investigating the brain regions that support task performance and the effect played by neuromodulators known to be involved in social behaviour (e.g. oxytocin). Furthermore, it will be investigated whether a similar social conformity effect can be observed in other areas of decision making. Elucidating these mechanisms is highly relevant for understanding psychiatric disorders associated with social dysfunction, such as autism. In

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of genes regulated by S-nitrosylation of HDAC2 during radial neuron migration. 12 Jul 2011

The generation of the laminar structure of the cerebral cortex relies on the radial migration of post mitotic neurons. This proceeds under the control of extremely precise regulatory networks requiring input from multiple extracellular signalling pathways and the co-ordinated expression of nuclear factors that result in specific programmes of gene expression. Recently, in the Riccio lab, we have shown that S-nitrosylation of HDAC2 is required for polarization and radial migration of cortical neurons during the formation of the cerebral cortex. A screen was carried out to identify genes regulated by S-nitrosylation of HDAC2 during cortical neuron migration. Druing this project, 2 candidate genes identified by this screen will be selected and their role in cortical development will be characterised. Key goals which have been set in order to achieve this include the following: 1) Verifying that these genes are upregulated in response to HDAC2 S-nitrosylation. 2) Characterisation of candidate genes expression in vivo 3) Analysis of candidate gene promoter and interaction with HDAC2 4) Characterisation of the function of the candidate genes in cortical neuron polarization and migration, which will include the generation of 2 knockout mouse lines.

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Cellular and network mechanisms of pattern separation in the dentate gyrus. 06 Jun 2011

This project will investigate how hippocampal dentate gyrus granule cells process synaptic inputs from the medial and lateral entorhinal cortex (MEC and LEC). I will determine how particular activity patterns in MEC and LEC are translated into granule cell population activity in vitro by selectively activating neurons in MEC and LEC using optogenetic stimulation of presynaptic neurons. The results of these experiments will be used to help us interpret subsequent in vivo recordings from granule cells in awake mice navigating in a virtual reality (VR) environment. Both in vitro and in vivo data will be used to construct models to help us to understand the link between cellular processing and behavioural pattern separation.

Amount: £11,835
Funder: The Wellcome Trust
Recipient: University College London

The role of auxiliary transmembrane proteins in AMPA receptor targeting in neurons. 06 Jun 2011

To investigate the types of AMPA receptor auxiliary proteins that regulate targeting of the receptors to axonal and presynaptic sites, to determine whether these differ from auxiliary proteins involved in receptor targeting at postsynaptic sites, and to understand their role in the regulation of transmitter release.

Amount: £23,306
Funder: The Wellcome Trust
Recipient: University College London

Synaptic and neuronal determinants of network function: Application of new optical and computational tools. 02 Jun 2011

Developing a mechanistic understanding of brain function is a central aim of neuroscience. I will investigate how synaptic and neuronal properties, together with network structure, control network synchrony and perform rapid information processing in the cerebellar cortex. To do this I will take advantage of powerful new optical and computational methods that I have developed, together with anatomical, electrophysiological and genetic approaches. The initial focus will be on properties of synap tic signaling in inhibitory interneurons, because they are poorly understood and my recent work suggests that electrical synapses between interneurons play a key role in desynchronizing network activity. I will build on this by examining why electrical signalling is excitatory in some cells and inhibitory in others. High-speed 3D 2-photon imaging will be used to measure network synchrony and investigate how it is controlled. By characterizing the input-output properties of synapses and neurons I will also determine the computations performed on sensory information. Biologically detailed network models will then be used to link neuronal computations and network structure to information processing at the network level. Key predictions from these network models, about the way information is represented and processed, will be tested by imaging the cerebellar cortex of intact animals.

Amount: £2,755,846
Funder: The Wellcome Trust
Recipient: University College London

Pain intensity, pain location and pain modulation: a combined neurophysiological and psychophysical approach. 03 Mar 2011

Pain is a complex subjective experience, most often caused by the activation of the nociceptive system. This project aims to investigate the neural bases of three cardinal aspects of pain perception: where it is (spatial localization), how much pain there is (intensity) and how it can be modulated by other somatosensory input (touch-pain interactions). Previous work on pain perception has been limited by poor control of pain stimuli and unreliable psychophysical techniques. We will resolve these problems by applying new fast, feedback-controlled laser stimulation, and improved subjective judgement methods, in a series of experiments with healthy volunteers. First, by investigating spatial acuity of pain, we will ask whether pain is more profoundly spatial than classically thought. By comparing its spatial precision to that of touch, we explore the possibility of shared spatial representations between the two senses. Second, we will develop improved pscyhophysical methods for reporting pain intensity, and then use these to better identify neural correlates of pain intensity using modern neuroimaging techniques. Finally, we combine this knowledge about spatial and intensity aspects of pain, to invest how nearby touch can inhibit pain. This basic understanding of pain mechanisms will have direct implications for clinical pain treatment.

Amount: £257,755
Funder: The Wellcome Trust
Recipient: University College London

Thymus transplantation for the treatment of Complete DiGeorge syndrome. 07 Mar 2011

Without intervention, complete DiGeorge syndrome (DGS) results in fatal immunodeficiency, as a result of absent thymic stromal function. Recent therapies focus on transplantation of non-MHC-matched thymic epithelium. This project will investigate the importance of MHC-restriction in immune reconstitution and self-tolerance in DGS patients treated with transplantation of thymic epithelium. To test if appropriate MHC expression in thymic epithelial transplants is necessary for efficient T-cel l immunity and tolerance-induction, we will compare the ability of T-cells from DGS transplant patients to activate and proliferate in response to MHC (+antigen) of host- or donor-origin. We will also establish in vitro and mouse in vivo models to address this question. We will compare tolerance induction in human thymus reaggregate cultures in which the epithelial and haematopoietic components are either MHC-matched or mismatched. To assess the impact of MHC-matching on immune reconstitution i n vivo, we will generate models in which athymic mice reconstituted with human haematopoietic stem cells, are transplanted with human thymic epithelium, expressing either MHC matched or non-matched to the haematopoietic component. In addition, to test if a gene-therapy approach to MHC-matching would be beneficial, we will test if we can improve reconstitution by lentiviral-transduction of matched MHC into thymic epithelial cells.

Amount: £408,095
Funder: The Wellcome Trust
Recipient: University College London

Activity-dependent trafficking of mitochondria to synapses by Miro1. 07 Oct 2010

This proposal will study the mechanisms that control the trafficking of the energy providing mitochondria within neurons, and how this relates to neuronal development and connectivity. Using imaging, molecular and cell biological techniques, combined with mouse transgenic approaches we will determine the molecular mechanisms underlying the activity-dependent subcellular positioning of mitochondria in neurons. We will examine how the mitochondrial calcium-sensing GTPase Miro1 acts as a molecul ar switch to regulate mitochondrial movement and distribution. How Miro1-dependent mitochondrial trafficking regulates neuronal migration and morphogenesis will also be determined in addition to the role of Miro1 in regulating the formation and maintenance of synapses and dendritic spines. A key goal will also be to determine if different roles exist for constitutive versus activity-dependent control of mitochondrial transport by Miro1 in these processes. These studies will significantly adv ance our understanding of the molecular mechanisms that control mitochondrial localisation in neurons and the role that activity-dependent mitochondrial trafficking plays in regulating neuronal morphogenesis and connectivity.

Amount: £410,528
Funder: The Wellcome Trust
Recipient: University College London

Imaging Pain in the Developing Human Brain. 22 Jun 2011

The aim of this research is to understand the development and plasticity of human pain processing, with a particular translational focus on improving clinical assessment and treatment of infant pain. When and how the human brain begins to process pain is fundamental to our basic understanding of human development and to paediatric clinical care. The key goals of this proposal are: (i) Undertsand the neuro-developmental mechanisms that underlie the beginning of human pain perception (ii ) To use fMRI to identify cortical and subcortical structures activated by noxious stimulation in the developing human brain? (iii) To investigate how noxious-evoked brain activity, spinal cord activity, and behavioural and autonomic responses are developmentally regulated? (iv) To establish whether morphine is an effective analgesic for procedural pain in newborn infants?

Amount: £646,654
Funder: The Wellcome Trust
Recipient: University College London

Agency, mental capacity and criminal responsibility in mental disorder. 18 Nov 2010

The project aims to elucidate the relationship between mental capacity and criminal responsibility in order to explore moral issues concerning the way people with a psychiatric diagnosis are treated between these two legal contexts. The project will develop a framework that both clarifies and evaluates current practices in the assessment of capacity and culpability in English law. The descriptive element of the project will use legal and philosophical analysis to identify the features of age ncy centrally, features of belief systems, motivational systems and control that are currently held to be relevant in determinations of capacity and culpability in English law, with a focus on drawing out the points of difference between the two. The normative element of the project will be concerned with evaluating moral, political or other potential justifications for the identified differences in assessments of capacity and culpability. By bringing attention to this question, and producin g a framework that makes recommendations for these areas of law, the project aims to have an impact on the way that features of mental disorder are taken into account in judgments regarding capacity and criminal responsibility.

Amount: £165,464
Funder: The Wellcome Trust
Recipient: University College London

Gynaecology in the Medical Texts of Ancient Mesopotamia from the 1st Millennium BC 13 Jan 2011

The primary goal of the proposed research will comprise an up-to-date edition of the corpus of the gynaecological cuneiform texts from 1st millennium BC Mesopotamia, consisting of transliterations, translations and a philological commentary. The text edition will form the basis for a comparative and context analysis of the corpus: the specific features and contents of the gynaecological corpus will be investigated, but also internal and external references and information for the socio-cultural contexts in which the gynaecological texts were written down and used, and the factors that have contributed to their form and features, will be analysed. Here, the position of gynaecological texts within the 'stream of tradition' of Mesopotamian medicine, the cultural belief system and social practice, will be investigated, concentrating on a) the specialists, healers and practitioners involved in treating women who contributed to the formation and transmission of the gynaecological texts, b) the concepts of the female body, the functional processes of the female sexual organs, and the specific gynaecological complaints and problems found in these texts, c) the ways of treating and healing women described in these texts.

Amount: £91,781
Funder: The Wellcome Trust
Recipient: University College London

The role of cervical innate immunity in preterm birth. 20 Jun 2011

The ultimate aim of this research is to reduce the number women delivering prematurely. The study has two aspects that are of particular clinical relevance: (1) it seems likely that early identification of women who are at risk of bacteria triggered PTB will be essential to intervening in a timely fashion ? phenotyping maternal antimicrobial defences at an early gestation offers a logical way to do this; (2) the idea of therapeutically augmenting cervical antimicrobial activity using vector mediated gene delivery to cervical epithelium is a highly novel approach that has the potential to prevent ascending bacterial colonization of the placenta and membranes. As such, the project is poised at the interface of clinical and basic science and may make a significant contribution to reducing the risk of preterm birth and subsequently both neonatal morbidity and mortality, and the serious long term disability associated with prematurity.

Amount: £215,215
Funder: The Wellcome Trust
Recipient: University College London

Notch and APRIL-mediated drug resistance in distinct molecular subgroups of multiple myeloma. 20 Jun 2011

Multiple myeloma is an incurable cancer, hence overcoming drug resistance is key to designing effective therapies. Different molecular sub-groups exist and we have recently shown that proliferation of primary MM cells in response to A Proliferation-inducing Ligand (APRIL) is sub-group specific. We believe that there are similar differences in drug resistance mechanisms. This work will investigate the interactions of APRIL and Notch pathways in mediating drug resistance and seek differences betwe en molecular sub-groups. Compounds targeting both the APRIL and Notch pathways are under clinical investigation, however off-target effects contribute to toxicity. By defining the role of each pathway, and their synergy in distinct molecular sub-group/s, we will be able to target our compounds to disease subgroups that will derive the most benefit. We have optimized an in vitro culture system that is able to maintain primary myeloma cells in culture for several days. Using this system, we will s et up assays employing both primary tumour cells and cell lines, exposed to anti-myeloma agents in the presence of APRIL and/or Notch ligands. Standard assays for cell survival and apoptosis will be used to assess drug resistance, and pathways will be investigated by blocking compounds, Western analysis and genetically modified stromal cells.

Amount: £223,026
Funder: The Wellcome Trust
Recipient: University College London

The transition from unconscious to conscious visual perception in the intact and damaged human brain. 20 Jun 2011

Clarifying the processes that determine the transition from unconscious to conscious perception is a central theme in visual awareness research. Emotionally-significant or familiar stimuli have modulatory influences on this perceptual transition, but such influences can be disrupted in perceptual and affective disorders. This research project will investigate the neural mechanisms underlying such modulatory effects on awareness in healthy human subjects as well as patients with focal brain lesio ns and congenital disorders of face perception. Presentation of a different image to each eye leads to spontaneous alternations in perceptual experience without any change to the external visual stimulus. Face stimuli with parametrically manipulable emotional and familiarity traits will be presented under such conditions of bistable perception. Structural and functional magnetic resonance imaging, magnetoencephalography, transcranial magnetic stimulation, and pharmacological intervention, will b e used to explore the neural structures and mechanisms enabling emotional significance and familiarity to influence visual awareness. This project will provide new insight into the mechanisms through which emotion or familiarity-related information can modulate awareness. It is anticipated that findings from this work will directly enhance understanding of impairments in the specific patient groups studied, but will also have a wider relevance to understanding other perceptual and affective dis orders.

Amount: £166,957
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

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