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University of Cambridge

Results

Structural and functional studies of regulatory assemblies and macromolecular machines. 19 Apr 2010

Many macromolecules in the cell function through multi-component assemblies whose activities can affect complex processes. We propose to study representative assemblies that play central roles in the regulation of gene expression and the coupling of metabolic pathways, and that comprise the machinery of transmembrane transport: Gene expression. Orchestrated turnover of mRNA is a key determinant of gene regulation. A critical role in regulating the balance and composition of mRNA transcripts is played by the multi-component RNA degradosome in Escherichia coli, effecting the coordinated expression of many genes from diverse metabolic pathways. We have solved several structures of the degradosome components and are investigating their interactions. We will study the structure and function of the complete assembly and of the analogous exosome, to explore how the machinery has evolved to meet the requirements of an expanded genome. Metabolism. We are continuing to investigate multi-enzyme systems, such as 2-oxoacid dehydrogenase, building on our structure determination of a subassembly and identification of a new mechanism of intersubunit-communication. Transport. We are investigating the movement of drugs and proteins across biological membranes. We will continue studies of a variety of energy-driven transporters, their assembly and mechanism, based upon our crystal structures.

Amount: £342,635
Funder: The Wellcome Trust
Recipient: University of Cambridge

Lipodystrophy-A paradigm for elucidating pathogenic mechanisms in the metabolic syndrome. 02 Jun 2010

My project has four themes: 1) Characterising the phenotype and molecular properties of two novel forms of lipodystrophy due to mutations in two lipid droplet proteins, perilipin and CIDEC. Perilipin s biological role is well documented so I will define the human phenotype associated with the mutations and characterise the biological properties of the mutants. The biological function of CIDEC is poorly understood, so I will characterise the mutant and explore the protein s biology including d etermining its precise localisation, its structure and identifying interacting proteins. 2) To use patients with genetically defined forms of lipodystrophy to explore questions relating to more common diseases - a) To understand the mechanisms of adaptive thermogenesis in lipodystrophy using humans and animal models. b) To identify the major sources of fatty acids responsible for fatty liver and dyslipidaemia? c) To establish if mitochondrial dysfunction, a feature of T2DM, is a cause or conseq uence of insulin resistance? 3) To identify novel genetic causes of lipodystrophy using next generation sequencing platforms. 4) To establish protocols for adipocyte differentiation of induced pluripotent stem cells. These cells will be invaluable tools for characterising the consequences of novel and unidentified forms of lipodystrophy and, ultimately for therapeutic replacement strategies.

Amount: £1,200,001
Funder: The Wellcome Trust
Recipient: University of Cambridge

"A programme of events by Mary Fissell in Cambridge" to be held in Cambridge form January to July 2011 13 Jul 2010

We seek support to bring Professor Mary Fissell to Cambridge to strengthen and enhance our programme on 'Generation to Reproduction', the core activities of which are supported by a Strategic Award (2009-14).

Amount: £3,900
Funder: The Wellcome Trust
Recipient: University of Cambridge

British Society for the History of Science Postgraduate Conference 2010 to be held on 5-7th January 2010 30 Nov 2009

Network building, development of presentation skills and exchange of feedback are the central objectives of this meeting, to be supported by sessions encouraging early career scholars to consider their professional options. This meeting provides a supportive environment in which postgraduate students in the history of science, technology and medicine can convene. Delegates can practise their presentation skills outside their home institution, gain conference experience and meet peers from across the world. This not only creates a forum for feedback on work in progress, but also allows graduate students to develop their own professional network. Two skills sessions allow delegates to consult senior academics on questions relating to career development. These sessions focus on academic publishing and the museums sector, and will encourage participation from all delegates, including those not presenting a formal paper. A third postdoc-led session raises awareness of the outreach and education activities headed by the BSHS. These sessions encourage delegates to consider and investigate a range of career options. While the focus of the meeting is on encouraging interaction between graduate-level scholars, these three sessions and a.drinks reception will provide opportunity to discuss experiences with more experienced academics who may be able to offer advice.

Amount: £2,550
Funder: The Wellcome Trust
Recipient: University of Cambridge

Anglo-Jewish women and obstetrics 1730-1780 13 Jul 2010

My project is crystallized into four principal research questions. First, how did immigrating to England (where the 'obstetric revolution' first took hold) during a period of such flux in reproductive care- for example, the publication of the forceps and the development of other obstetrical tools- affect the established reproductive rituals of Jewish women? Second, given that the 'medicalisation' of childbirth was also, of necessity, a 'secularisation' of many aspects of 1 the childbirth ritual, how was the religiosity of Jewish women affected by the advent of 'man-midwives', obstetric physicians, and maternity hospital? Third, how did the experience of birthing differ across the internal class structures of the Jewish community? Finally, how did the Anglo-Jewish woman's experience of the 'obstetric revolution'- given an insular community, a separate doctrine, and rabbinical law - compare to that of her Anglican counterpart?

Amount: £2,886
Funder: The Wellcome Trust
Recipient: University of Cambridge

British and German Eugenicists in Transnational Context, 1930-50 13 Apr 2010

This project strives to provide a new contextualisation of the interwar eugenics movement with special emphasis placed on the impact of hereditarian thought on international policy-making discussions and processes. This analysis will be concentrated on the three most active national eugenics movements prior to the Second World War: that of the United States, Great Britain, and Germany. It was researchers in these nations that developed most of the underpinnings of eugenics and the formal structures responsible for its influence on state policy. Despite the largely uniform early strength of eugenics in these countries, by 1939 they had reached differing policy achievements. American state governments were the first legislative bodies to implement eugenic laws including sterilisation of the mentally defective. In Germany the newly unified state considered a sterilisation act during the Weimar Republic but this was rejected due to the Catholic opposition. It was only after the rise of Hitler's government that eugenics found fertile ground for its policies. While the example of the United States seems to indicate that a combination of wealthy backers and grass-roots support for eugenics was most critical to its success at the local level and the German example appears to confirm the intuition that nondemocratic governments could most easily implement eugenic policies, the British case provides an interesting counterexample. Despite the fact that Francis Galton and many of the field's most significant early researchers were British there was little pressure to implement eugenic ideas in practice. The campaign for sterilisation in the early 1930s failed to attract powerful supporters and failed quietly, effectively marking the end of attempts to pass eugenic policies prior to the War. This project aims to seek new explanations for the successes and failures of eugenics in policy-making circles by examining these in international contexts. For instance, there is evidence that the British campaign for sterilisation had been launched largely because of pressure from German and American delegates at international congresses who sought to push British representatives from leadership positions by demonstrating their comparative impotence in lobbying for domestic policies these nations had already passed. Similarly, after the promulgation of the 1933 German sterilisation law American eugenicists feared that their continental colleagues were rapidly pushing their governments toward eugenic policies that might threaten American power. The result was a short-term idolisation of Nazism in American eugenic circles. Thus, this research will provide a network analysis of the international connections and indeed rivalries that affected the production of eugenic laws in the countries under consideration. This aspect has never been considered by scholars and will enhance the understanding of how and why eugenics was able to have such a significant impact in some countries while remaining excluded from the corridors of power in others.

Amount: £1,917
Funder: The Wellcome Trust
Recipient: University of Cambridge

Intra and inter-host evolution of equine and swine influenza viruses. 07 Jul 2009

There is a vast body of knowledge on the biology and epidemiology of Influenza viruses, but the relationship between epidemic processes and viral evolution at all scales is not well understood. A critical feature of this problem is the need to quantitatively link influenza dynamics at the individual and population levels. Current technologies of genome sequencing make tackling this problem feasible by allowing determination of the extent and structure of intra-host genetic variation of a viral p opulation within a single individual. Combining this with animal transmission studies makes it uniquely possible to consider how this variation is then transmitted in a natural host. In this application we propose a combination of whole genome sequencing and antigenic cartography studies, using equine and swine influenza viruses in their natural hosts, to understand essential issues such as i) the role of cross protective immunity in shaping viral diversity; and ii) the proportion of intra-host diversity that is passed at transmission. This project will provide a science base essential for understanding the implications of decisions made in the formulation of vaccines against all mammalian influenza viruses.

Amount: £242,785
Funder: The Wellcome Trust
Recipient: University of Cambridge

Developmental programming of insulin resistance and obesity in offspring of diet induced obese mothers. 21 Jul 2009

To investigate the mechanisms involved in the developmental programming of obesity and insulin resistance in peripheral and central tissues of offspring of obese mothers using a mouse model of maternal diet-induced obesity.

Amount: £152,005
Funder: The Wellcome Trust
Recipient: University of Cambridge

The reprogramming of sperm compared to somatic celi neclei. 08 Jun 2009

The sperm cell has a highly specialised developmental programme and gene expression profile. However, in order to allow embryo-specific gene expression, the paternal genome has to undergo reprogramming. Reprogramming is also crucial for a proper embryonic development during another process -somatic cell nuclear transfer (SCNT). Normally, a cell once differentiated, cannot de-differentiate. However, it has been shown that it is possible to de-differentiate a cell experimentally. When somatic cell nuclei of Xenopus laevis were transferred into enucleated eggs, healthy embryos were generated. However, in contrast to fertilization, SCNT seems to be significantly less efficient in embryo generation [1]. But can mechanisms of reprogramming after fertilisation be directly compared with those that follow SCNT? Probably not, as both processes occur differently. In order to investigate the comparative efficiency of fertilisation events and SCNT in offspring generation, I would treat the sperm in the same way as the somatic cell is treated in the SCNT procedure and examine the developmental capacity of such embryos. If the results prove that the sperm is indeed more efficient than a somatic cell nucleus in producing normal embryos, I would investigate what is so special about the sperm making it so efficient. This would lead to an identification of sperm-specific factors responsible for the efficiency of the reprogramming after fertilization. Ultimately, further characterisation of these factors and mechanisms of their action should shed light on similarities/differences between reprogramming after fertilization and SCNT. It would be a major contribution to understand what controls the ability, especially of nuclei from differentiated cells, to lead to normal embryo development.

Amount: £151,984
Funder: The Wellcome Trust
Recipient: University of Cambridge

Blood groups between transfusion testing, population genetics and anthropology: Arthur Mourant and human diversity in postwar Britain 11 Jun 2009

To provide a context for Mourant's career, I will begin by examining the pre- and interwar context of blood-group research, in particular the links forged between clinically driven blood-group research, anthropology and population genetics in Britain, by focusing on the Galton Laboratory Serum Unit. I will then study the funding, remit, and activities of Mourant's Blood Group Reference Laboratory (BGRL), Nuffield (Anthropological) Blood Group Centre and Serological Population Genetics Laboratory (SPGL). I will examine how these activities related to his anthropological projects and explore the extent to which the more theoretical work depended on, and was justified by, his clinically oriented testing. Building on previous analyses of the representational techniques of early blood-group anthropologists, I will examine how Mourant, and the field of physical anthropology more generally, responded to new population genetic definitions of race, as formalized especially by the 1951 revised UNESCO Statement on Race, and how this affected the politics of Mourant's disciplines. I will examine how Mourant's project was received by different audiences - clinicians, geneticists, anthropologistsand the general public. Explaining the fate of his laboratory will cast light on the changing status of blood-group research.

Amount: £80,532
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 31 Aug 2009

In infant humans and small mammals, brown adipose tissue (BAT) functions as a tissue for thermoregulation. This is achieved through its ability to uncouple oxidative metabolism from ATP synthesis; thus facilitating the conversion of caloric energy, especially fats, into heat. With the recent discovery that BAT is present in biologically relevant amounts in both lean and obese adults, the possibility of activating BAT as a means of increasing caloric loss in obese states are being investigated. When BAT is activated, there is a simultaneous increase in both fatty acid oxidation and synthesis. In addition, the synthesized fatty acids are extensively modified, including acyl-chain elongation and desaturation. We postulate that the ability of BAT to modify fatty acids is crucial to its function. Specifically, fatty acid chain length and saturation helps determine its intracellular fate; either towards oxidation, storage or other cellular compartments. The aim of this study is to investigate the role of fatty acid composition on BAT metabolism and asses the impact of this alteration on whole body energy balance and thermoregulation. Fatty acid elongation will be disrupted by altering the expression of Elovl6 (Elongase of very long chain fatty acid-6) in both in vitro and in vivo models. Supporting this, increasing amounts of published data supports the role of fatty acid chain length in obesity and insulin resistance. In addition, our preliminary data suggests that Elovl6 is highly expressed in BAT and its expression increases with BAT activation.

Amount: £244,665
Funder: The Wellcome Trust
Recipient: University of Cambridge

PhD Programme for Clinicians at the University of Cambridge: "Generation of 'translation ready' ground state human induced pluripotent stem cells and cardiomyocytes as a prelude to disease modelling in cardiovascular medicine". 18 Feb 2009

The generation of induced pluripotent stem cells from somatic cells brings the possibility of translational applications in regenerative medicine, disease modelling and drug screening a step closer. However current derivation methods remain inefficient, unpredictable and clinically unsafe. In order to maximise the translational potential of iPS cells in clinical medicine, these methods must be optimised. I will establish a 'translation ready' iPS cell by identifying the most efficiently reprogrammable of a number of human somatic cells including dermal fibroblasts, keratinocytes and adipose tissue. Clinically safer non-viral gene delivery methods will also be developed. Attempts will then be made to capture and maintain ground state pluripotency by deriving iPS cells in variations of the recently described 2i/LIF conditions shown to suppress early differentiation signals, reduce epigenetic restriction and improve iPS derivation efficiency in mouse and rat iPS cells. The resulting iPS cells will be characterised in terms of gene expression, epigenetic profiles and differentiation potential. Ultimately, iPS cells derived from a patient with a known monogenetic cardiac channelopathy such as long QT syndrome will be differentiated into cardiomyocytes and functionally examined by patch clamp in collaboration with electrophysiology colleagues to prove their suitability for the modelling of monogenetic cardiac channelopathies.

Amount: £4,129
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge: Generation of patient specific stem cells towards cell based therapy of inherited metabolic diseases of the liver. 18 Feb 2009

To evaluate the potential of patient specific induced pluripotent stem cell (iPSC) derived hepatocytes to generate cells for cell transplant therapy in treating inherited metabolic diseases of the liver, a new chimeric mouse - human diseased liver model will be created. The first step will involve taking hepatocyte / skin fibroblast cells from Alpha 1 Antitrypsin deficient patients and reprogramming them in vitro to iPSCs. These cells will then be differentiated to hepatic progenitors and used to repopulate the liver of the FAH-/- mouse to produce a novel chimeric mouse - human liver model. The same patient specific iPSC derived hepatocytes will be genetically corrected and engrafted into the mouse model to try and achieve functional correction of the disease phenotype. By this we aim to 1) produce a new human hepatocyte cell line for Alpha 1 Antitrypsin deficiency 2) produce a new chimeric mouse - human liver 3) produce a new patient specific corrected human hepatocyte cell line from (1) 4) show proof of principle that engrafting the corrected cell line could be a therapeutic strategy towards treatment of A1ATD and other inherited metabolic disorders of the liver.

Amount: £62,831
Funder: The Wellcome Trust
Recipient: University of Cambridge

Modulation of human basophil function by schistosomiasis. 19 Oct 2006

IgE is key to both anti-helminth immunity and allergic hypersensitivities. Although cell-bound allergen-specific IgE mediates many allergy symptoms, highlevels of circulating IgE and FceR-bearing cells found in chronic helminth infections do not cause systemic clinical effects, even when infected individuals are exposed to intravenous allergen challenge, as when schistosomes are drug-killed in situ. We propose that examination of human basophil behaviour/biology in the context of chronic intravenous helminthiasiswill provide new insights into the pathophysiology and immunology of both helminth infections and allergic diseases. We focus on basophils because [a] they are key cells in allergic inflammation; [b] basophils can be readily accessed in human blood; [c] we have evidence that basophils are in a partially suppressed/controlled state in human schistosomiasis, which changes with chemotherapy. Preliminary data shows that we can successfully numerically, phenotypically and functionally study basophils from individuals in schistosomiasis endemic areas, in relation to parasitological and serological parameters. In schistosome-infected Kenyans, by systematically relating basophil function (differentially-regulated histamine, leucotriene C4, and IL-4 release) in the presence and absence of plasma, to changes in basophil phenotype numbers and circulating factors, we will identify suppressor/control mechanisms important for both anti-parasite immune responses and severity of allergic hypersensitivities. We will also investigate the modulating roles of 'infection' plasma factors in passively sensitizing/blocking normal basophil function.

Amount: £335,355
Funder: The Wellcome Trust
Recipient: University of Cambridge

Determination of heterogeneity of glycoprotein and tegument proteins in HSV1, and the functional significance of the HSV1 gH-integrin interaction. 24 Apr 2007

Determining the extent to which populations of complex enveloped viruses exhibit compositional heterogeneity is of fundamental importance for understanding aspects of virus entry, morphogenesis and pathogenesis. We will determine the variation in terms of glycoprotein and tegument composition in populations of Herpes Simplex virus Type 1 (HSV1) at the single particle level using highly-sensitive fluorescence-based confocal spectroscopy. We will subsequently compare heterogeneity profiles of vi rus populations propagated under conditions that are biologically relevant to HSV1 infection, and will determine the influence of tegument and glycoprotein deletions on virion-to-virion compositional make-up. We will also determine the functional and biological significance of the interaction between HSV1 glycoprotein H (gH) with host cell integrin molecules. We have found that purified recombinant gH protein binds to cells expressing alpha-v-beta-3 integrins, and now wish to ascertain the rel evance of this interaction, both in terms of the entry of HSV1 into specific cell types, and the ability of HSV1 to induce intracellular signalling pathways.

Amount: £468,298
Funder: The Wellcome Trust
Recipient: University of Cambridge

A multi-user facility for cell imaging and manipulation. 27 Apr 2006

This application is for equipment to provide facilities for cell manipulation, imaging and analysis. The proposal consists of six core projects. These projects are linked by a focus on molecular and cellular mechanisms that operate in development to produce patterned arrays of differentiated cells and by the exploitation of genetic techniques using simple model organisms. The specific goals of these projects are 1) to understand the way in which progenitor cells become polarised (Palacios); 2), 3) and 4) to understand how different cell fates are established and how these lead to stereotypic cell interactions that determine complex networks in the nervous system (Bate, Landgraf) or in tissues with functionally segregated domains (Skaer); 5) and 6) by using the patterns of differentiated cells revealed by segmentation (Akam) and by arrays of sensory bristles (Simpson), to uncover the molecular basis for divergence between closely related species that drives evolutionary change. The research programmes of all six groups require advanced techniques for image acquisition and analysis and for the manipulation or ablation of cells and subcellular structures. The most efficient and cost effective way to provide these resources is in the form of shared facilities to which each group has access.

Amount: £690,900
Funder: The Wellcome Trust
Recipient: University of Cambridge

Stem cell differentiation-recapitulation of development? 30 Aug 2006

Stem cell differentiation - recapitulation of development?

Amount: £143,077
Funder: The Wellcome Trust
Recipient: University of Cambridge