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iNKT cells as key mediators of inflammation - Dissecting the role played by iNKT cells in haematopoiesis. 18 Jan 2010

The overall aim of this research programme is to investigate the role played by invariant NKT cells in myelopoiesis; in influencing the differentiation of cells along the myeloid lineage, key players in inflammation. Research will be divided into three complementing programmes: Objective 1: Identification of leukocyte populations which require iNKT cells for differentiation Objective 2: Test the hypothesis that iNKT cells enhance the speed of haematologic recovery Objective 3: Dissect the molecular mechanisms of iNKT cell-mediated MDSC differentiation Significance: iNKT cells are at the interface between the innate and adaptive immune responses. Understanding the mechanisms by which iNKT cells modulate haematopoiesis and inflammation will be of importance to develop strategies to stimulate myelopoesis and harness iNKT cell activation during inflammation.

Amount: £23,687
Funder: The Wellcome Trust
Recipient: University of Oxford

Environmental enrichment and recovery following anterior thalamic lesions. 15 Feb 2010

The research has two parallel aims. The first is to study the rescue of memory loss after brain injury using lesions of the anterior thalamic nucleus in rats to model ?diencephalic amnesia?. In particular, the research will determine the functional impact of environmental enrichment on recovery and examine potential mechanisms for the beneficial effects that have so far been described. The second aim is to identify clinical cases with amnesia and damage to diencephalic structures and determine the potential for rehabilitation procedures based on the enrichment programme with rodents.

Amount: £35,320
Funder: The Wellcome Trust
Recipient: Cardiff University

'The influence of network activity on the spatiotemporal receptive fields of mouse V1 neurons'. 15 Dec 2009

The project will investigate the influence of neuronal population activity on receptive field properties of individual neurons in mouse visual cortex at different developmental ages in order to understand how this region of the brain becomes specialised for sensory processing. Particular emphasis will be made on characterising the synaptic mechanisms which shape receptive fields in response to different types of visual stimuli.

Amount: £14,138
Funder: The Wellcome Trust
Recipient: University College London

'Mechanisms of transplanted photoreceptor precursor migration and integration'. 15 Dec 2009

To examine the mechanisms by which transplanted photoreceptor precursor cell migrate into the recipient retina and to compare these mechanisms with those by immature photoreceptors in embryonic development

Amount: £39,182
Funder: The Wellcome Trust
Recipient: University College London

The role of FAPa-expressing stromal cells in therapeutic vaccination in a mouse model of pancreatic ductal adenocarcinoma. 15 Feb 2010

Mesothelin as a potential target for immunotherapy- project aim 1 The fir.;t objective of this project is defining an antigen that could be used in the vaccine. Several TAA have already been described to be uniquely expressed in human pancreatic cancer and not in the normal tissue. On~ of the most promising candidates is mesothelin - GPI anchored differentiation antigen that was found in all mesotheliomas an~ pancreatic aden9carcinomas (22), and approximately 70% of ovarian cancer.; and 50% of lung adenocarcinomas [23]. Additionally, mesothelin expression was restricted to pancreatic adenocarcinomas, whereas adjacent normal pancreas did not stain for mesothelin. Mesothelin as an antigen has already been used in allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumour vaccines to treat patients with surgically resected adenocarcinoma of the pancreas (24). 3 out of 14 patients developed post-vaccination delayed-type hypersensitivity (OTH) response to autologous tumour, which was associated with prolonged survival. To find whether mesothelin is also expressed in KPC mouse model we isolated RNA from lung, pancreas from healthy mice and POA from tumour-bearing animals. Our preliminary qPCR data suggest that 3 out of 5 tumour.; that were examined showed high mesothelin RNA level (Fig. 3). In order to verify this result on protein level tumour sections will be stained with anti-mesothelin antibody. However, as there are few antibodies (Ab) directed against mouse mesothelin, it is required to screen commercially available Ab and validate then on western blot. Preliminarily, cancer cell lines isolated from PDA tumours can be used for those tests. Cancer/Testis antigens as potential targets for immunotherapy- project aim la (contingency plan) Mesothelin is not the only potential PDA-associated antigen. Cancer/testis antigens (CTA) are immunogenic molecules expressed in normal tissues, but restricted to placenta, testis, fetal ovary, germ cells and placenta, as well as in a wide variety of tumours. There are approximately 150 CT As identified to date ( strictly regulated by epigenetic mechanisms. Vaccines containing the CT antigens- MAGEA and NY-ES0-1/CTAGIB- are utilized in patients with melanoma as well as lung and ovary cancers. Generation of viral vectors for immunization- Vaccinia-project aim 2 In this project, to mount an effective anti-tumour T cell response, a vaccine strategy utilizing ~ poxvirus as TAA delivery vehicles in combination with T -cell costimulatory molecules will be introduced. The attenuated strain of Modified Vaccinia virus Ankara (MV A) is widely used. as a safe non-replicating recombinant vaccine vector in humans and other mammals. Among the first TAA successfully used for immunization with VV are carcinoembrionic antigen (25), prostate-specific antigen [26] and many melanoma-associated antigens. Generation of viral vectors for immunization-gamma-herpesvirus- project aim 2 Herpesviruses persist latently in the infected host indefinitely effectively evading the immune response. Sporadic reactivations lead to release of infectious virions and facilitate spreading to new host. As y-herpesvirus (?HV) reactivation is only observed in immunosuppressive conditions, it suggests that immune system is able to control the infection. It was demonstrated that more potent antiviral response mediated by antigen-specific COS+ T cells was found in persistent ?HV infection [27)[28). Moreover, during latent infection with ?HV -68 increased turnover rate of CD8+ T cells indicates that these cells are restimulated with antigen. Using recombinant methodology sequence of the antigen of interest will be inserted in place of ovalbumin in both vectors. Infection of LL20VA-bearing mice with ?HV -OVA maintained high level of SIINFEKL-specific CD8+ T cells (data unpublished), which controlled tumour growth when F APa ablation was performed. Assessment of immune response to vaccines project aim 3 Before performing therapeutic vaccination on tumour-bearing mice it is necessary to evaluate the effect of immunization. Cellular response will be assessed by performing killing assay or by studying the profile of major cytokines (IL-2, IL-4, IL-10 and IFN-y). In order to evaluate CDS+ T cell killing antigen-expressing cell line with matching MHC will be used and chromium release will be monitored to detect lysis. EVALUATION OF TUMOUR GROWTH- PROJECT AIM 4 For the purpose of measuring tumour growth, tumour volume will be quantified by 30 ultrasonography [ 17]. 30 ultrasound provides a new method for the objective quantitative assessment of stromal echogenicity and vascularity as well as blood flow within the tumour. Moreover, the biggest advantage of this technique is its non-invasiveness, which enables assessment of the effects of therapy without sacrificing animals. This will be done in collaboration with Tuveson's lab.

Amount: £21,929
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interactions and structures in antigenic variation. 20 Oct 2009

Recent discoveries have changed traditional views of antigenic variation in trypanosomes1. It is important now to define fundamental facts at the host-parasite interface in the chronic phase of infection. My aims are to answer the following questions: 1. How sequence-related are VSGs that are expressed sequentially in the chronic phase of infection, and do they cross-react serologically? 2. If they are cross-reactive, how do trypanosomes expressing them survive? 3. What are the epitope specificities of responding antibodies? 4. What is the structure of exposed epitopes of the variant surface glycoprotein, and to what extent do naturally present mutations alter them? Answers to those questions will help answer a core question about antigenic variation: 5. What are the contributions to antigenic variation of total gene switching, segmental gene conversion, and point mutation?

Amount: £6,075
Funder: The Wellcome Trust
Recipient: University of Glasgow

The roles for Slit/Robo proteins in the and regulation of chemokine function and cell movement. 30 Nov 2009

Since the discovery of its importance in the development of the nervous system, the Slit/Robo signalling pathway has become more and more remarkable among pathways of intercellular communication. Initially identified for roles in axon guidance, it is now clear that the Slit/Robo system regulates a complex range of other biological processes involved in the development and growth of various organs and tissues. Moreover, the Slit/Robo signalling axis has also been implicated in cancer. Most recently a role for Slit/Robo in regulating chemokine-dependent leukocyte migration during immune and inflammatory responses, has been demonstrated. In spite of the clear biological importance for Slit/Robo in these diverse biological systems, there remain many unanswered questions of relevance to Slit/Robo function. It is the aim of this project to take 2 approaches to studying the biology of this system. Specifically we propose to examine, in detail, roles for Slit/Robo signalling in the control of leukocyte migration and in addition, we propose to use biochemical and cellular approaches to detail the mechanism of Slit/Robo transmembrane signalling. The aims of our project are: 1) To examine the roles for Slit/Robo in the regulation of chemokine-dependent leukocyte migration 2) To examine the cellular mode of action of Robo by directly imaging its cell membrane positioning and oligomerisation status and its association with chemokine receptors or their downstream signalling components.

Amount: £3,000
Funder: The Wellcome Trust
Recipient: University of Glasgow

Transport and signalling of cell adhesion molecules and their role in motor neuron survival. 13 Jul 2010

We previously demonstrated that histone H2A is phosphorylated at Ser129 in response to DNA damage by the Mec1p and Tel1p kinases in yeast. Others demonstrated that the analogous residue in mammalian chromatin (Ser139 on histone H2AX) is also phosphorylated in response to DNA damage, and H2AX is a tumour suppressor gene in mice, demonstrating that this is a central event in eukaryotic DNA damage responses. Yet, it is still not entirely clear how this phosphorylation event functions to facilitate survival after DNA damage occurs. We therefore propose to further investigate the function of H2A phosphorylation using three approaches. First, we will systematically characterize the phosphorylation event by analyzing the timing, kinetics, and genetic dependence of phosphorylation in different cell cycle phases, growth phases and ploidy backgrounds. Second, we will examine the fate of phosphorylated H2A. Third, we plan to investigate the effect of phoshpoinositol signalling on H2A phosphorylation and DNA damage responses. Finally, we will integrate these studies with ongoing research in the lab in which we have identified proteins that bind specifically to phosphorylated H2A. Together, these studies will advance our understanding of this highly conserved event in particular and of DNA damage responses in general.

Amount: £5,565
Funder: The Wellcome Trust
Recipient: University College London

The interplay between the Notch and Wnt signalling pathways in somitogenesis. 20 Oct 2009

The interplay between the Notch and Wnt signalling pathways in somitogenesis This project aims to investigate the potential crosstalk between the Notch and Wnt signalling pathways in the important process of somitogenesis. It is well established now that the Notch pathway plays a crucial role in somitogenesis during vertebrate embryogenesis in a variety of species. More recently it was shown that the Wnt pathway is also required for this process in the mouse embryo. It was also reported that Wnt may play a role upstream of Notch in this process. The first aim of the project is to confirm and extend preliminary findings that Notch may be upstream of Wnt in chick somitogenesis. The second aim of the project is to examine the level of interplay between the two pathways in both the mouse and the chick embryo. Establishing how the Notch and Wnt pathways control somitogenesis will be an important step in understanding how this process is regulated.

Amount: £4,808
Funder: The Wellcome Trust
Recipient: University of Dundee

A Legal and Ethical Analysis of Research Risks Imposed on Children Involved inCluster Trials With More Than Minimal Risk Conducted Between1999-2010 in Kenya. 03 Jun 2010

1) Review and categorise research risks children are exposed to in different types of 'cluster trials', and explore how these risks are currently regulatedif indeed they are; 2) Test the traditional account of proxy consent and best interests within this context, 3) Examine how the concept of 'minimal' risk is used to see whether it serves to protect or exploit children's multiple vulnerabilities during cluster trials. Key output & goals: mapping and inventory of clinical trials with children andof regulatory framework, critical review of regulatory framework for research involving children, practical suggestions for strengthening local approaches, the engagement of local stakeholders in the review and in the suggestions.

Amount: £134,290
Funder: The Wellcome Trust
Recipient: University College London

Equitable Access to Human Genetic Resources - Balancing Benefit Sharing and Undue Inducement. 03 Jun 2010

The broader research question (How can access to human genetic resources, suchas blood or DNA samples, be governed to achieve justice for developing countries?) requires the completion of the following tasks: Detail the justice issues arising from accessing human biological resources in developing countries (e.g. contribution to research without access to resulting, life-saving products). Map identified justice issues onto relevant justice theories (e.g. cosmopolitanism, human rights framework). The specific research question (How can benefit sharing be achieved without undue influence through inappropriate inducement?) necessitates the completion of the following tasks: Describe existing benefit sharing mechanisms. Explore what types of benefit sharing mechanisms, if any, amount to undue inducement. Examine current proposals for overcoming the problem (e.g. expanding the CBD) The PhD will close a remaining gap in the current research on benefit sharing by producing recommendations for the equitable access to human biological resources in developing countries.

Amount: £94,551
Funder: The Wellcome Trust
Recipient: University of Central Lancashire
Amount: £76,508
Funder: The Wellcome Trust
Recipient: University of Exeter

Senility before Alzheimer: Old Age Mental Health in British Medicine, Politicsand Culture, 1840- 1914. 10 Jun 2010

This project will explore how 'senile dementia' was understood before Alzheimer in latenineteenth century Britain in medical, political and popular contexts. It will look to the period 1840- 1914 as a time of intense political interest in both the elderly and the mentally ill, and as the time when the word 'senile' shifted, from a value-neutral term describing the general condition of old age, to a more negative term with significant connotations about mental incapacity. Key goals: - To assess how the mental changes of old age were described and explained by psychiatrists. - To examine the relationship between published ideas and practice in increasingly crowded asylums. - To investigate the relationship between the political discourses on pensions, retirement and the welfare of the aged poor, and mental aspects of ageing. - To survey representations of the 'senile' in 'popular culture', and to examine the relationship between these representations, medical models and political concerns. The final product will be a broad survey of the images and meanings of 'old age' in Victorian society and culture, and the place of 'mental capacity and behaviour' within them.

Amount: £77,731
Funder: The Wellcome Trust
Recipient: University of Warwick

'The great class which lies between': Provision for the non-pauper insane in Ireland, 1830-1900. 10 Jun 2010

Through a close survey of the records of selected private and district asylums, Commission of Lunacy reports, and official records, the project will explore the domestic and institutional provision for the Irish non-pauper insane from c.1830 to 1900, a period marked by significant socioeconomic change. It will assess whether the emergence of a strong middle-class in this period informed interactions between gender, religion, identity, and insanity, and question whether underlying medical, legal and lay explanations of mental illness and its predisposing factors in this group differed from those attributed to pauper patients in Ireland. The project will reflect on the anxieties that were prompted among local and national authorities, the medical profession and families, inside and outside the asylum, while devising management strategies. It will then assess the impact of these strategies upon patient and family experiences of insanity. This project will consider whether some Irish asylums operated as a mixed economy' of care and will explore how class and religious divisions were played out among the patient and staff populations within the asylums thereby contributing to emerging debates on presence of emotional communities' within asylums. The main outputs comprise a PhD thesis, three articles two policy-related and a workshop.

Amount: £79,537
Funder: The Wellcome Trust
Recipient: University College Dublin

'Unable to give any account of himself': Male experiences of Stanley Royd asylum, Wakefield, 1880-1900. 10 Jun 2010

The project examines the influence and interplay of popular and scientific explanations for male mental illness during the period 1880-1900. My first key goal will be to gather a sample for statistical analysis, enabling me to identify any significant differences between the experiences of male and female patients at Stanley Royd asylum e.g. duration of illness prior to admission. This will allow me to compare and place my findings within the existing historiography, and highlight any points of particular interest that merit further investigation e.g. the reasons given at admission for male/female committal. Secondly, I will examine medical casebooks for insights into the opinions of doctors, families and acquaintances on the situation of the patient: if there are clear judgements on a male patient's state of mind which flow from contemporary ideals of 'manliness', and if treatments draw explicitly upon such ideas e.g. the prescription of strong beer and physical work to remedy a man's 'weak' nature. Thirdly, papers and lectures by asylum doctors will be consulted. As well as investigating the possibility of biological explanations reinforcing or challenging existing gender stereotypes, these will chart the development of biological psychiatry at Stanley Royd that influenced researchers further afield.

Amount: £85,445
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Transgenic animals: Genetically modified mice in Britain and the United States, 1970-2000 10 Jun 2010

To explore the history of GM mice, I will begin by studying technical innovations in mammalian embryology and reproductive physiology in the 1970s. In particular, I will consider how the techniques travelled, through multiple exchanges between laboratories in Britain and the US, and how this research was variously combined with recombinant DNA technologies developed in the 1970s to produce multiple transgenic mice in 1980-1. Then I will explore the parallel lines of research on embryonic carcinoma (EC) and embryonic stem (ES) cells in the 1970s and 1980s. To assess the effect of the new kinds of animals on the infrastructure of their breeding and supply, and the stabilisation of their production, I will use as a case study the MRC Radiobiology Unit (Mammalian Genetics Unit since 1995) in Harwell, a stock centre and research facility for mouse experimentation, in the 1980-1990s. I will pay special attention to criteria for genetic modification and negotiations over the status of the mice. Finally, to analyse the (contested) use of GM mice as models of human disease, I will consider the induction of breast cancer through oncogene insertion.

Amount: £85,708
Funder: The Wellcome Trust
Recipient: University of Cambridge

The pathology of the emotions 10 Jun 2010

My research will show how melancholy in nineteenth-century Britain was conceptualised as a disease of the emotions situated in the brain through the influence of German psychiatry and neurology. There are five main goals to this project: - To address a lack in existing historical scholarship as no comprehensive study of nineteenth-century melancholy exists. - To demonstrate how the understanding of melancholy as a disease of the emotions was facilitated by two key developments: Firstly, the creation of 'emotions' as a psychological category within the emergent evolutionary paradigm, and secondly the growing influence of physiology and neurology on psychiatric thought and practice which involved understanding its functions through the concept of 'mental reflex'. - To show how emotions were produced as symptoms of melancholy and made into a useful psychiatric category. - To explore, through a close reading of case reports and patient letters, - To consider what the implications were of this biomedical cerebral melancholy for how 'normal' and 'pathological' emotions came to be understood and defined in the late nineteenth century.

Amount: £91,369
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Clinical PhD Programme at the University of Cambridge: 'Functional characterisation of responses to DNA damage in human cells.' 21 Sep 2010

Failure of accurate DNA damage sensing and repairing mechanisms manifest as a variety of human diseases including cancer. Cytotoxic chemotherapy and radiotherapy remain the most beneficial in terms of cancer treatments and largely act through the generation of DNA damage. Accuracy and efficiency of DNA damage detection and repair requires the recruitment and subsequent post-translational modification of various proteins. Ubiquitylation and sumoylation are highly dynamic and reversible enzymatic processes that play crucial roles during the execution of DNA damage sensing and repair. Further characterization of the enzymes involved in these processes is required in order to fully understand how the DNA damage response (DDR) is regulated and has the potential to provide new therapeutic targets. PIAS SUMO E3 ligase enzymes are necessary for human cells to respond appropriately to and effectively repair DNA double-strand breaks. ZIMP7 and ZIMP10 are two PIAS -like proteins that also contain a SP-RING/Miz zinc finger domain that potentially confers E3 ligase activity. Very little previous research has been focused on these proteins. I have demonstrated that both ZIMP7 and ZIMP10 are recruited to sites of DNA damage induced by laser micro-irradiation in cultured human cell lines. My goal now is to characterize the precise functions of ZIMP7 and ZIMP10 in the DDR.

Amount: £221,618
Funder: The Wellcome Trust
Recipient: University of Cambridge

Clinical PhD Programme at the University of Cambridge: 'Defining the origin and fate of Fibroblast Activation Protein (FAP) expressing cells in health and disease'. 21 Sep 2010

A population of tumour stromal cells, identified by Fibroblast Activation Protein (FAP) expression, are essential for suppressing the immune response directed toward the tumour. FAP+ cells are present in inflamed tissues, in healing wounds, during embryological development and recent work from our laboratory has found them in a wide range of normal adult tissue, including muscle, bone marrow and the kidney. Depleting FAP+ cells in mice leads to significant weight loss and skeletal muscle loss. Clearly FAP+ cells have a fundamental role in both health and disease. Their function in different tissues is not clearly defined but raises the question of whether they are all related. Are all FAP+ cells derived from a common lineage? Understanding the origins and fates of these cells will have significant implications for developing effective cancer therapies but may also provide evidence of a cell linking inflammation, healing and tissue specific regeneration. Key goals 1. Generate a BAC Transgenic (Tg) mouse in which FAP+ cells, and all their progeny, can be conditionally marked to express yellow fluorescent protein in vivo. 2. Use the Tg mouse to determine whether FAP+ cells in the tissues are derived from a common embryonic precursor and whether FAP+ cells can become FAP- in vivo. 3. Define the origins of FAP+ cells in acutely and chronically inflamed tissues.

Amount: £240,390
Funder: The Wellcome Trust
Recipient: University of Cambridge

Bayesian inference using a norm based face coding scheme in humans 21 Sep 2010

Recently large amounts of evidence have accrued suggesting that the human brain often supports optimal Bayesian inference, but it has not been shown that this is so in face recognition. In parallel a leading hypothesis for the encoding of faces is the so-called norm coding scheme, whereby each face is defined by its position in face-space. In face-space the average face sits at the origin, and, in a Bayesian interpretation of inference in this context, the peak of the prior probability distribution should correspond to this rather than another face. By using a multivariate analysis, sensitive to the fine structure of fMRI responses, we hope to characterise these implicit probability distributions inthe aIT (anterior inferotemporal cortex) of human subjects, and show that whensubjects hallucinate a face in noisy stimuli this is the average face ratherthan another. This supports a Bayesian interpretation of the norm based scheme, since otherwise any face might be hallucinated . Finally, we aim to show that while face and anti-face (its opposite in face space) can be differentiated in aIT (the face identifier), this cannot be donein the fusiform face area (the face detector).

Amount: £259,443
Funder: The Wellcome Trust
Recipient: University of Cambridge