- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 07 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Adaptive decision templates in the human brain 30 Nov 2016
Interacting with the surrounding environment depends on our ability to extract meaningful patterns from incoming streams of sensory information. Learning and experience are known to facilitate this skill; yet, we know little about how the brain extracts structure and generalises this knowledge to novel settings. Here, I propose to test the brain mechanisms underlying structure learning using contrasting tasks that involve learning structure in space vs. time at different levels of complexity (simple vs. complex feature contingencies). I will use computational modelling to interrogate the processes involved in learning behaviourally-relevant structures (i.e. decision templates). I will relate this system-level insight to multimodal neuroimaging to provide converging evidence for brain mechanisms that mediate learning specialisation and generalisation. I will exploit high-field imaging to test fine-scale decision templates in the visual cortex. I will combine 7T imaging with human electrophysiology (MEG/EEG) and interventions (TMS) to test for local and larger-scale brain circuits that retune decision templates through feedback and inhibitory interactions. Finally, I will test whether these mechanisms support our ability to generalise previous experience to novel contexts and tasks. This integrated approach will advance our understanding of the brain’s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.
We aim to elucidate the circuit mechanisms underlying three key computations essential for memory-based behavioral choice: 1) updating valences attached to sensory cues, when actual and expected outcomes differ; 2) computing the “value” for each action, based on multiple, conflicting cues; and 3) selecting one action and suppressing other physically incompatible competing actions. One obstacle to progress in this field has been the problem of identifying underlying circuits with synaptic resolution, and causally relating structural motifs to their proposed function. Both insects and vertebrates have evolved cerebellar-like higher-order parallel-fiber systems specialized in forming large numbers of associative memories and in guiding memory-behavioral choice. However, no synapse-resolution wiring diagram of any such system has been available to guide analysis and inspire understanding. We have recently mapped the synaptic-resolution wiring diagram of one such system, the insect mushroom body, in Drosophila larva, which reveals multiple novel circuit motifs and provides clues about learning and decision-making models and their neuronal implementation. An exquisite genetic toolkit available in this model system allows selective manipulation of individual neuron types to establish causal relationships between their activity and behavior. We are now in a unique position to causally relate the identified structural motifs to their function.
Determination of the prevalence breast cancer predisposition genes in South East Asian women and development of an Asian polygenic risk assessment tool 05 Jul 2016
Breast cancer is rising rapidly in Asia and is the most common cause of cancer related deaths in Malaysia. Notably, whereas 80% of breast cancer in the UK occurs in post-menopausal women, only 40% occurs in post-menopausal women in Malaysia, and the proportion of risk attributable to genetic factors is likely to be correspondingly higher. In the absence of population-based screening, targeted screening provides a cost-effective alternative to reducing breast cancer mortality. Unfortunately, there remains a significant gap in knowledge and access to counseling and testing of BRCA1, BRCA2 and other cancer predisposition genes in most of Asia. With the decreasing cost of genetic testing, there is an opportunity to bridge that gap. We plan to: (1) characterise the prevalence of genetic susceptibility to breast cancer in the South East Asian population in Malaysia and Singapore; (2) provide risk estimates for BRCA1 and BRCA2 in our population; and (3) calibrate risk assessment models to accurately predict an individual’s risk of carrying germline alterations and their risk of cancer. The findings of this research will enable shared decision making and inform the development of appropriate management to ensure that healthcare resources can be used efficiently for targeted screening and prevention.
Connectomics, establishing comprehensive neuronal wiring diagrams at the resolution of single synaptic connections, is still in its infancy. Although most neuroscientists are confident that connectomics will eventually have a major impact, doubts remain about when this will happen. We propose a project that within 4 years could transform an important field of neuroscience – the circuit basis of learning and memory – by reconstructing the olfactory memory circuits of Drosophila. A consortium of laboratories at HHMI Janelia has generated a complete serial section transmission EM volume of an adult female Drosophila brain. This 106 TB volume (100x larger than any previously imaged whole brain) will have a major impact on over 200 laboratories working in Drosophila neurobiology. We will reconstruct input and output neurons of the primary associative learning centre, the mushroom body, along with selected upstream layers bringing teaching signals and downstream layers mediating descending control of behaviour. This will reveal the complete network and synaptic organisation of a memory centre, whose logical principles, including sparse coding, dopamine-dependent plasticity, valence segregated by neuronal population, and network recurrence, are all relevant to mammalian brains. This will enable a wealth of experimental circuit studies as well as piloting large-scale, geographically-distributed connectomics.
Regulatory potential of repeat elements in the evolution of tissue-specific transcription 05 Jul 2016
The human genome, like all mammalian genomes, is in large part composed of decayed--but once active--repeat elements, many of which carry tissue-specific regulatory information. We hypothesise that repurposing of repeats has been critical for creating tissue-specific transcriptional regulation. Our research plan is an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across the recent placental mammalian radiation.
Centrioles, at the core of centrosomes, orchestrate structure and function in the interface and mitotic cell. Here we aim to understand how centriole duplication is controlled. This requires Plk4 kinase to phosphorylate Ana2 in part so it can bind Sas6. Here we address how phospho-Ana2 interacts with other core procentriole components, Dragon, Ana3 and Rcd4 and how these events are spatially regulated to achieve duplication. Second, we aim to characterize how centriole to centrosome conversion is regulated giving newly formed centrioles competence to duplicate and nucleate cellular microtubules. We will determine how Polo kinase regulates formation of the Cep135, Ana1, Asl network essential for centriole conversion. We will also assess roles of Polo and Plk4 in anchoring peri-centriolar material (PCM) to the centriole and Plk4’s role at the peri-centriolar satellites to mobilise centrosomal molecules. Thirdly, we address how centrosomes can organise membranous vesicles. We focus upon Dragon, a molecule present in the centriole and the Golgi apparatus, and Rosario, counterpart of lysozyme-like vesicle protein LYST, required to evenly distribute centrosomes in the syncytial embryo. We will characterize the process whereby primordial germ cells form in the syncytium, an event triggered by interactions of centrosomes with the embryo’s polar cytoplasm.
University of Cambridge - Metabolic and Cardiovascular Disease
University of Cambridge 4 Year PhD Programme - Developmental Mechanisms
University of Cambridge - Metabolic and Cardiovascular Disease
The formation of liver tissue during embryogenesis requires dynamic interactions with endo the lial and mesenchymal cells of the microenvironment, which can be recapitulated in vitro to direct the production of hepatocytes from pluripotent stem cells. The adult liver is characterised by low cellular turnover, yet it is endowed with a facultative Lgr5+ stem/progenitor population that drives tissue regeneration following damage and can be expanded in vitro as 3D liver organoids. Here, we aim to study adult non-parenchymal liver lineages – liver sinusoidal endothelial cells, hepatic stellate cells, portal myofibroblasts and Kupffer cells – as functional components of the microenvironment, or ‘niche’, in progenitor -mediated regeneration. We will characterise the spatiotemporal association of putative niche cells with Lgr5+ progenitors and differentiated progeny throughout regeneration, and perform a whole-genome transcriptomic analysis on selected niche lineages. Making use of organoid co-cultures that incorporate niche cells from regenerating livers, we will validate the ability of the niche to support Lgr5+ progenitor proliferation and differentiation. The molecular effectors of the pro-differentiation niche will be identified and the cells will be ablated in transgenic mice to confirm their niche role in vivo. These studies may elucidate novel mechanisms of liver healing and result in the establishment of organotypic liver cultures.
Virtually nothing is known about the exact molecules responsible for orchestrating haematopoietic stem cell (HSC) self-renewal and lineage differentiation. Identifying molecules governing stem cell self-renewaland differentiation will not only provide a greater insight into stem cell biology but may also uncover novel therapeutic targets for cancer since cellular mechanisms regulating clonal expansion in cancer are likely analogous to those operating in stem cells. My PhD will focus on the identification and assessment of molecular drivers of stem cell fate choice and has two aims: 1) Identification of genes directing lineage choice in HSCs. Two approaches will be taken to identify candidates: i) Clustering of single HSC gene expression profiles and functional transplantation outcomes based on cell surface marker expression, allowing the correlation of functional outcome with a particular gene expression profile. ii) Gene expression profiling of single HSCs and their direct progeny in conditions which support either self-renewal or promote differentiation. 2) Functional validation of gene candidates in vitro and in vivo with respect to effects on self-renewal and differentiation. This will be achieved by perturbing gene function and by performing a series of single cell functional assays.
Investigating the epigenetic mechanism behind transgenerational inheritance in germ cells of mice 30 Sep 2016
Poor nutrition leads to an increased risk for disease, which may be passed on to subsequent generations with a normal diet. This non-genetic mode of inheritance is not well understood. The goal of my project is to investigate this epigenetic mechanism by focusing on the inheritance of altered DNA methylation in sperm from a genetic mouse model of abnormal folate metabolism (Mtrrgt model). Folate is part of the one-carbon metabolism necessary for DNA methylation. Previously, the Watson lab reported that when either maternal grandparent carried the Mtrrgt mutation, their wildtype grandprogeny displayed developmental phenotypes and dysregulated DNA methylation. How this epigenetic instability is inherited to disrupt development is unclear. My hypothesis is that abnormal DNA methylation patterns caused by Mtrr deficiency escape epigenetic reprogramming, are passed onto subsequent wildtype generations and disrupt developmentally-important gene expression. My specific goals are: 1. To prove that Mtrrgt mutants have not acquired additional genetic mutations. 2.To determine whether alterations in DNA methylation patterns in sperm from the Mtrrgt model are present and inherited. 3.To morphologically and molecularly analyze testes structure and spermatogenesis in Mtrr mutants. Understanding mechanisms of epigenetic inheritance will help us predict how our environment affects our descendants’ disease risk.
Obesity: Exploiting Genomes for Novel Insights 06 Dec 2016
What are the mechanisms by which genes influence an individuals propensity to obesity. I study animal models to find answers to that question. I will study the link between genes and obesity in two complementary research streams. Firstly, I will build on my recent discovery of an obesity-associated POMC mutation in animal models which disrupts hypothalamic leptin-melanocortin signalling. Deep phenotyping of eating behaviour and physiology in the absence and presence of a synthetic MC4R agonist with the goal of defining the contribution of POMC-derived peptides to energy homeostasis. Secondly, I will use genome-wide association studies in animals to find further genetic determinants of obesity. Their relevance to humans will be tested in large patient cohorts with both rare, severe obesity and common obesity, and putative obesity loci studied in relevant cell models. Preliminary data has shown this approach is successful.
I aim to take advantage of the cichlid fish of Malawi to study the interaction between transposable elements, non-coding RNAs, epigenetics and heritability. This is in line with the overall goal of my Investigator Award. I believe this system to be superior to equivalent experiments we might conduct in mice. This is due largely to the high phenotypic diversity and low genomic diversity of these fishes. At the time of writing of my Wellcome Trust Investigator Award the cichlid model was too immature to proceed with an experimental plan. Now we have the required genomics, RNomics and epigenetics (DNA methylation) are all in place
Computational tools for analysing developmental morphogenesis at the tissue-scale
To be submitted later
To be submitted later
Characterisation of the mitral annulus and its dynamics to inform materials choice for implant design in the surgical correction of degenerative mitral regurgitation 30 Sep 2016