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Award Year:
2014
Currency:
GBP
Recipients:
University of Cambridge

Results

Directly induced neural stem cells (iNSCs) for the treatment of progressive multiple sclerosis (PMS_iNSC). 13 Nov 2014

There is an urgent need to develop therapies that will cope with persistent inflammation and foster remyelination in the progressive phase of multiple sclerosis (MS). Stem cells possess a pleiotropic therapeutic potential that may be key in counteracting the variety of maladaptive processes that lead to disease progression/disability in MS patients. Before clinical application, we need to identify the most promising sources of stem cells for transplantation and further define their putative me chanisms of action in MS. Throughout the course of this fellowship I aim at characterizing tissue-specific, autologous, stably-expandable Neural Stem Cells (NSCs), and in so doing will assess their therapeutic properties in relevant mouse models of MS. Induced NSCs (iNSCs), obtained from mouse fibroblasts, will be transplanted in MOG-induced EAE (a model of chronic MS) and lysolecithin-treated mice (a model of focal demyelination). The in vivo assessments of immunomodulatory vs remyelinating p otential of iNSCs will be coupled by extensive ex vivo and in vitro co-culture studies. This preclinical data will allow our group to gain insight on the potential of iNSCs in modulating disease progression and further will facilitate the development of a solid preclinical platform designed to bring iNSC therapy into clinical practice.

Amount: £198,632
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms controlling peptide selection for immune recognition. 03 Dec 2014

I have discovered that TAPBPR is a novel MHC class I specific component in the antigen processing and presentation pathway. This work represents a major advance in the field of MHC biology. It is now essential to investigate the specific function of TAPBPR in the immune system in order to understand its role in health and disease. My key research goals are to: 1)Determine the role of TAPBPR in MHC I peptide selection. Techniques used will include sequencing the peptide repertoire presented to the immune system by mass spectrometry in wild-type and TAPBPR depleted cells, in vitro peptide exchange assays for TAPBPR function on MHC molecules, and T cell assays to assess the consequence of TAPBPR depletion on recognition of MHC by T lymphocytes. 2)Characterise the molecular mechanisms underpinning TAPBPR function. Experimental methods used will include affinity chromatography with mass spectrometry to identify other TAPBPR binding partners, solving a crystal structure of TAPBPR b oth alone and with MHC class I, and assessing functionality of mutated TAPBPR molecules. 3)Investigate the contribution of TAPBPR in infection control and autoimmunity. The role of TAPBPR in infection control will be determined by investigating the susceptibility of TAPBPR knockout mice to viral and bacterial infections. The contribution of TAPBPR in the pathogenesis of the spondyloarthropathies, the strongest autoimmune disease associated with MHC class I, will be determined by comparing t he functionality of TAPBPR variants found in patients to controls on HLA-B27 peptide presentation and immune recognition.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the spatiotemporal regulation of microtubule nucleation in Drosophila. 29 Oct 2014

Microtubules are dynamic polymers that have crucial roles in many eukaryotic cell processes. They are nucleated by multi-protein gamma-TuRCs that are concentrated at various MTOCs within the cell. Although most, if not all, of the gamma-TuRC components are known, it remains unclear how gamma-TuRCs are recruited to different MTOCs at different times during development and during the cell cycle. Moreover, it is not clear how each component functions in the complex. Previous studies have concentrat ed on specific gamma-TuRC components or cell types, and have often studied only mitotic processes. I will use Drosophila as a model to conduct a comprehensive in vivo analysis of gamma-TuRC biology in various cell types, including mitotic cells, developing oocytes and terminally differentiated neurons. Mutant and fluorescently tagged lines exist for most, but not all, of the gamma-TuRC components and I intend to complete this toolset using CRISPR, a novel and rapid genome engineering technique t hat works very efficiently in flies. By studying a range of cell types and examining the role of all gamma-TuRC components, I hope to gain a better understanding of how microtubule nucleation is regulated in space and time throughout animal development.

Amount: £912,868
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the molecular mechanisms of adult liver regeneration. 04 Jun 2014

In the intestine and stomach, organs with extensive self-renewal, Lgr5 marks adult stem cell populations that are constantly cycling. In the liver, an organ with limited cellular turnover but huge regenerative capacity, Lgr5 is not detected under physiological conditions. However, marks a new stem/progenitor cell population that gets activated upon damage and contributes to restore the tissue and reinstall homeostasis. The main goal of this proposal is to understand the molecular mechanisms, t hat following tissue damage, regulates the transition of adult liver cells from a quiescent to an activated state, from the role of the niche during this transition to the epigenetic changes triggering this activation. The main focus of this research plan will be: Plan1) Identify the quiescent cell/s that become activated cells during damage-regeneration; Plan2) Elucidate the niche for activated stem cells; Plan3) Identify the gene regulation mechanisms (epigenetic) involved in liver stem cell activation following damage. As liver disease and liver cancer are highly associated to liver damage, understanding the mechanism regulating stem cell activation holds promise to extend our knowledge not only of liver regeneration but also of liver disease and cancer.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Making scientific capacity in Africa: An interdisciplinary conversation (Application for co-funding with CRASSH, Cambridge). 14 Apr 2014

The applicant and collaborator, together with a faculty research group at Cambridge, have successfully applied for an interdisciplinary conference at the university's Centre for Research in the Arts Social Sciences and Humanities (CRASSH), on the 'Making of scientific capacity in Africa', to be held in Cambridge in June 2014 (13th-14th). This Conference is linked to the Faculty Research Group 'Civic Matter: Infrastructure as Politic' (http://www.crassh.cam.ac.uk/programmes/civic-matter-infras tructure-as-politic), part of which was a panel about African laboratories - 'Scientific infrastructure'. (http://www.crassh.cam.ac.uk/events/25117). The meeting brings together anthropological, historical, medical and other scientific perspectives, and drawing upon the experience gathered in large-scale collaborative African endeavours such as the THRIVE and CAPREx programs at Cambridge. (See website: http://www.crassh.cam.ac.uk/events/2484/) The CRASSH budget does not allow for overs eas participants, which given the subject area, would be a grave omission. We therefore seek travel funding for four African colleagues who have been particularly successful in the field of academic capacity building in relation to medical issues. They will present papers on their experience, adressing questions such as what key elements of academic and scientific capacity for Africa are, and what can be learned from past experience in order to enhance future capacity building.

Amount: £4,640
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £17,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology - Moritz Matthey 31 Mar 2014

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £51,654
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development of high-speed super-resolution STORM imaging for the large-scale analysis of transport, signaling and endocytosis in multicellular environments 04 Mar 2014

The goal of this research is to demonstrate that temporal focusing combined with two-photon absorption and photodynamic therapy can treat a tumour that is located within a mass of tissue. In year one, the goal will be to construct the optical setup, characterise it, demonstrate automated control of the illumination parameters, and demonstrate the ability to selectively illuminate regions of a test mass such as a dye-doped gel block. In year two, the goal will be to optimise the optical se tup, and selectively generate singlet oxygen at a defined site with high spatial resolution. Diagnostic imaging methods such as stimulated Raman scattering or optical coherence tomography will be investigated for incorporation. In year three, the effectiveness of the system will be tested on cell-lines in order to demonstrate that the cells can be selectively targeted. Diagnostic imaging will be finalised and incorporated, allowing a mixture of healthy and cancerous cells (taken from cell-lin es) to be differentiated, and the cancerous cells killed. The final year will be back in the UK; the system will be reconstructed (with any modifications deemed necessary). Subject to a successful outcome, applications will be made to test the system in animal models and possibly clinical trials.

Amount: £79,046
Funder: The Wellcome Trust
Recipient: University of Cambridge

Institutional Strategic Support Fund PHASE 2 FY2014/16 27 Oct 2014

Support senior/leadership and early career recruitment in key strategic areas in the Schools of the Biological Sciences and Clinical Medicine Provide early career support for recently appointed lecturers, or equivalent, in the Schools of the Biological Sciences and Clinical Medicine Provide bridging support for early career scientists who are between awards Support capacity building in bioinformatics for translational clinical research Provide support for state-of-the-art Technology Platforms Strengthen links between the biological/clinical and physical sciences through internships for interdisciplinary research Strengthen links between biological/clinical sciences and the social sciences and humanities through support for policy workshops Support Public Engagement around key areas of our scientific research

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £1
Funder: The Wellcome Trust
Recipient: University of Cambridge

Computational Analysis of Regulatory Mutations in Developmental Disorders 14 Jul 2014

Only one third of patients with severe developmental disorders, including neurodevelopmental disabilities, can currently be diagnosed with causative mutations within protein coding sequences. Non-coding mutations that disrupt normal gene expression in critical developmental genes likely explain a proportion of the undiagnosed patients. The focus of this PhD project will be the integration of sequence data from the Deciphering Developmental Disorders (DDD) project and the 100,000 Genomes project with annotations of regulatory function to better understand the role of regulatory elements in development. This computational analysis will generate hypotheses relating to specific variants in individual genomic functional elements and these hypotheses will be validated by a combination of molecular profiling of accessible tissues from relevant patients, genetic replication of association in additional patients with similar phenotypes, and modelling in mice of putative pathogenic mutations.

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

Temporal Regulation of Cortical Neurogenesis in Development and Evolution 23 Jun 2014

"The cerebral cortex is involved in a wide range of functions, from sensory processing and control of voluntary movement to language, thought and consciousness. Cortical neurons are produced during development in a temporally ordered progression from multipotent progenitor cells, with lower-layer neurons generated before upper-layer neurons. The molecular mechanisms regulating this temporal progression are not understood, although this process appears to be controlled largely by cell-intrinsic timing mechanisms that can be recapitulated in vitro. Notwithstanding considerable variation in cortical size and cellular components in different mammalian species, the temporal order of production of cortical neurons is evolutionarily conserved. The timing of this progression is however very different between species, scaling with body and cortical size; the cellular and molecular mechanisms underlying these evolutionary differences are currently unknown. This project will: (i) Characterise the molecular mechanism(s) of action of known lineage-progression regulators during human cortical development; (ii) Identify and characterise novel genes involved in regulating the temporal order of production of different cortical neuron subtypes during human development; (iii) Investigate and characterise any adaptations of the lineage-progression regulatory mechanism that might result in evolutionary differences in lineage-progression timing. "

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

Deciphering mechanisms of neurotransmitter specification in Drosophila melanogaster 23 Jun 2014

This project aims to uncover the logic of neurotransmitter specification in the developing central nervous system of Drosophila melanogaster. In the insect nervous system neuroblasts constitute the fundamental developmental units, each generating a defined set of nerve cells. Although the various neuroblast lineages have been well characterised in Drosophila melanogaster in terms of cell number, morphology, and position within a segment, for most lineages it still remains unknown what neurotransmitters the cells produce and by what mechanisms different neurotransmitter phenotypes are specified. The first objective of the project is to characterise the neurotransmitter type of neuronal lineages in the ventral nerve cord, focusing initially on a few lineages that the lab has direct genetic access to. The second objective will use the information gained about the principal patterning of neurotransmitter types in lineages to investigate the mechanisms by which neurotransmitter type is specified. Targeted DamID will be performed in collaboration with Tony Southall to uncover the genetic profiles of lineages that produce different neurotransmitters. The third objective will be to test candidate genes from the Targeted DamID for involvement in neurotransmitter specification, and thus understand the mechanisms by which this important element of neuronal functionality is established during development.

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

Identifying and understanding the function of trait associated non-coding variants 14 Jul 2014

In this project, I plan to expand on existing genome wide association study analysis techniques, to empower our ability to detect trait associated variants. The techniques will aim to target the ‘missing heritability’ and the current lack of knowledge surrounding the functionality of non-coding variants. This will be achieved by calculating, in an unbiased manner, the likelihoods of non-coding variants to control downstream gene products. In order to optimally evaluate the likelihood, I will impute publically available annotations into existing sizeable cohorts, for which whole-genome (or genotype) sequence data is available. These prior probability distributions will be subsequently incorporated into existing gene set test methods, in combination with multi-trait strategies. I will apply the developed method to existing cohorts, for which quantitative glycaemic and lipid trait measurements are available in an attempt to identify trait associated loci, which have not yet been uncovered. Additionally these likelihoods can be used to generate hypotheses, which explain how a variant mediates its effect on the observed phenotype. These theories will be subsequently tested, using methods that are able to elucidate causation from consequence and account for confounding factors.

Amount: £160,792
Funder: The Wellcome Trust
Recipient: University of Cambridge

Coated vesicle adaptors. 01 Apr 2014

Adaptors select cargo for inclusion into different types of coated transport vesicles. The best characterised of the adaptors are the AP-1 and AP-2 complexes, which are associated with clathrin-coated vesicles (CCVs) budding from intracellular membranes and from the plasma membrane respectively. We plan to look for new cargo sorting signals using libraries of random cytoplasmic tails, and for new sorting machinery using a combination of CCV proteomics and genome-wide siRNA library screening. In teractions between sorting signals and candidate adaptors will be investigated both structurally (in collaboration with David Owen) and functionally, using a number of novel assays such as CCV profiling and rapid inactivation of CCV machinery by rerouting to mitochondria. Questions we will address include how the GGA pathway interfaces with the AP-1 pathway, how SNAREs are sorted into CCVs, whether GGA-mediated trafficking contributes to the pathology of Alzheimer's disease, and how HIV-1 Nef hi jacks adaptors to down regulate MHC Class I and CD4 from the surface of virally infected cells.

Amount: £1,749,495
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms controlling polarised secretion at the immunological synapse. 01 Apr 2014

The aim of my research is to understand the molecular mechanisms that govern polarized secretion at the immunological synapse. We will use the CTL model with a clear trigger (TCR) and end-point (target cell death) to identify and characterize proteins that play a role in polarization and secretion as the immunological synapse is formed. Our specific aims over the next 5 years will be to (i) Map the order of events leading to secretion at the immunological synapse using rapid microscopy to compare the sequence of events leading to secretion in wild-type versus mutant CTL. (ii) Identify novel mechanisms contributing to polarised secretion in CTL by identifying genes up-regulated by Hh signaling that facilitate centrosome polarization; analyzing CTL derived from ciliary mutations that disrupt Hh signalling, gene-deletion mice from the Sanger screen and using proteomics to identify interactions with known proteins. (iii) Determine whether the lysosome itself plays a role in controlling polarization and secretion at the immunological synapse by asking whether TFEB regulates gene expression of proteins required for CTL secretion, and whether localized release of calcium from lysosomes via TPC1 and TPC2 controls any of the steps leading to polarized secretion from CTL.

Amount: £3,479,056
Funder: The Wellcome Trust
Recipient: University of Cambridge

Public Engagement provision 01 Apr 2014

The aim of my research is to understand the molecular mechanisms that govern polarized secretion at the immunological synapse. We will use the CTL model with a clear trigger (TCR) and end-point (target cell death) to identify and characterize proteins that play a role in polarization and secretion as the immunological synapse is formed. Our specific aims over the next 5 years will be to (i) Map the order of events leading to secretion at the immunological synapse using rapid microscopy to compare the sequence of events leading to secretion in wild-type versus mutant CTL. (ii) Identify novel mechanisms contributing to polarised secretion in CTL by identifying genes up-regulated by Hh signaling that facilitate centrosome polarization; analyzing CTL derived from ciliary mutations that disrupt Hh signalling, gene-deletion mice from the Sanger screen and using proteomics to identify interactions with known proteins. (iii) Determine whether the lysosome itself plays a role in controlling polarization and secretion at the immunological synapse by asking whether TFEB regulates gene expression of proteins required for CTL secretion, and whether localized release of calcium from lysosomes via TPC1 and TPC2 controls any of the steps leading to polarized secretion from CTL.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Public Engagement Provision. 10 Apr 2014

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £171,011
Funder: The Wellcome Trust
Recipient: University of Cambridge