- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 19 Mar 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Deciphering mechanisms of altered neurodevelopment in BAF complex intellectual disability disorders 06 Dec 2017
Intellectual developmental disorder (IDD) is a common yet poorly understood condition. Recent advances in genomic diagnostic technologies have revealed that disruption of genes involved in transcriptional regulation is a leading cause of IDD. Genes encoding the chromatin remodelling BAF swi/snf complex are among the most commonly mutated. Filling the knowledge gap between mutation and disease will contribute to improved patient care and to our overall understanding of human brain development. To that end, I will bridge the clinical and neurodevelopmental biology fields using patient-phenotype informed cellular models to investigate the molecular underpinnings of disease. I will perform deep-phenotyping of a cohort of patients with BAF-complex mutations, and correlate clinical and psychometric features with gene expression and epigenetic signatures in primary tissues. Alongside this clinical study, I will investigate the specific role of ARID1A, an essential BAF complex subunit, in neurodevelopment. Those investigations, performed in induced pluripotent stem cell (iPSC) models of human neurodevelopment, will inform subsequent studies in iPSCs generated from patients. Detailed understanding of clinical outcomes will improve patient management, and integrating the cellular and molecular defects in in vitro models with clinical and molecular phenotypes in patients will help establish predictive preclinical models for translational research.
R-loop coupled chromatin regulation 10 Apr 2018
Non-canonical chromatin structures are emerging as important components of gene regulation. One example, RNA-DNA hybrid structures known as R-loops, occur frequently in many genomes. Initially studied with respect to genome instability, they have now been linked to transcriptional regulation, heterochromatin formation and recombination. But exactly what regulates R-loop dynamics, and how R-loops influence local chromatin states to affect a wide range of chromatin processes is still poorly understood. Deriving mechanistic understanding of R-loops from genome wide analyses is difficult. We will therefore focus on one functionally important R-loop and exploit a genetically tractable system and a wealth of information to develop deep mechanistic understanding into the regulation and role of an R-loop. We will identify novel factors that stabilize and resolve the R-loop, and establish how their functions are integrated. We will investigate whether the R-loop sets up a transcription-replication conflict that propagates heterochromatinization of the locus, thus setting the expression state. We will also dissect if R-loop dynamics and a gene loop influence promoter dominance to co-ordinate sense and antisense transcription. Active collaborations will enable a broad set of approaches to be used and concepts to be compared between organisms.
Thick filament-based mechanisms for the dynamic regulation of contraction and relaxation in the heart 21 Feb 2018
Recently it has become clear that, whilst the canonical calcium/thin filament-based pathway provides a start signal for contraction in skeletal muscle, its strength and speed are largely controlled by structural changes in the myosin-containing thick filaments. I now propose to test the hypothesis that thick filament regulation plays a similar key role in the dynamic control of contractility in heart muscle, by adapting and extending the methods I successfully applied to study thick filament-based regulation in skeletal muscle. I will use a fluorescence-based approach to characterise the structural dynamics of thin and thick filaments during activation and relaxation of isolated cardiac trabeculae and cardiac myofibrils. I will investigate the role of thick filament regulation and mechanical stress in determining the physiological rate of force generation and of relaxation in the heart, and how these rates are modulated in response to its functional requirements, including the stronger contraction observed after increased venous filling (the Frank-Starling law of the heart). The results of these studies are likely to lead to a new paradigm for the physiological control of contractility in the heart that will underpin future studies of the changes in that control in heart disease and potential therapeutic corrections.
By 2050 10 million lives could be claimed a year by drug resistant infections. We must develop new strategies for antimicrobial drugs. Often in infections bacteria form biofilms, requiring concentrations of antibiotics up to 1000 fold higher to be treated. Cyclic dipeptides are molecules produced by organisms in all domains of life, and their function is unknown. They can inhibit bacterial growth and/or biofilm formation, albeit by undetermined mechanisms. The majority of the biological effects caused by cyclic dipeptides are inter-species and in some instances inter-kingdom, mediating host pathogen interactions. I will study enzymes from gram-positive and gram-negative bacteria involved in the production of different cyclic dipeptides. I will characterise each enzyme biochemically and structurally and determine their substrate scope. I will produce novel molecules, which will be used to disrupt growth and biofilm formation in Pseudomonas aeruginosa and Staphylococcus aureus growing alone and in bacterial co-cultures. I will combine genetic and chemoproteomic approaches to determine the molecular targets of cyclic dipeptides in P. aeruginosa and S. aureus. I will validate targets using bacterial mutants and biochemical assays. The identification of molecular targets of cyclic dipeptides will unveil crucial pathways for inter-species interactions and identify novel antimicrobial targets and molecules.
Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.
Role of the haematopoietic stem cell niche in pre-leukemic clonal haematopoiesis and myelodysplatic syndromes 21 Feb 2018
Myelodysplastic syndromes (MDS) are prototype pre-leukemic conditions that initiate in haematopoietic stem cells (HSC). These are characterized by clonal HSC expansion, inefficient production of mature blood cells and a higher propensity to progress to acute myelogenous leukaemia. Multiple studies suggest that MDS-HSCs are highly dependent on the bone marrow niche. It is possible that leukemic stem cells exploit the normal remodelling capacity of the niche to create a self-reinforcing leukemic environment, thereby favouring leukaemia development. However the molecular mechanisms involved in this process are still largely unknown. This project aims at identifying the signalling networks involved in the bidirectional crosstalk between MDS-HSCs and specific niche cells, and how this contributes to MDS pathogenesis in both mouse and human. A multidisciplinary approach will be used, combining transcriptomic analysis of niche cells and HSCs, 3D-imaging of the bone marrow and computational modelling. I will investigate which essential interactions between MDS-HSCs and their niches are responsible for their competitive advantage over normal HSCs. These studies have the goal of ultimately disrupting these interactions as a novel therapeutic avenue for MDS, a disease that currently has very few treatment options.
What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vector. 21 Feb 2018
There is a fundamental lack of understanding regarding how tick-borne viruses replicate in ticks and how the tick innate immune system controls infection. My proposal will focus on tick-borne SFTS phlebovirus, its overarching goals are to understand how tick-borne viruses interact with ticks and tick cells and how this facilitates transmission to mammalian hosts. To achieve my goals, I will carry out in vitro and in vivo studies that can be divided into three specific aims: (i) to elucidate the basic molecular biology of tick-borne virus replication, (ii) to define the innate immune factors that control virus replication in the tick cell environment and (iii) to examine whether virions derived from tick or mammalian cells have similar biological properties and virulence? I will conduct in vitro experiments in tick cell lines to examine virus-vector interactions. Importantly, I will also establish unique tick colonies and infection capabilities for the UK. Through combined cell culture approaches and in vivo animal experiments I will investigate the replication of phleboviruses in the live tick for the first time. I will also explore the infectivity of virions derived from different sources and assess if tick-derived viruses are more virulent to mammals in animal inoculation studies.
East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians 10 Apr 2018
East London Genes & Health is a long term programme for population genomic medicine research in British-South Asian adults. Unique features include high rates of health deprivation, especially diabetes, cardiovascular disease and mental health; high rates of consanguinity (including human knockouts, rare predicted loss of function variants occurring as homozygotes); local excellence in e-health record access/analysis; and recall for further research by genotype/phenotype. In this proposal we wish to continue and expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health - to reach 100,000 volunteers; add value to the Genes & Health resource through SNP array genotyping all samples; and by sequencing and analysing consanguineous individuals. This will then enable us as a collaborative team to ask detailed research questions about adult-human knockouts. Specifically we will perform population based analyses of naturally occurring adult-human knockouts to better understand their population genetics, and (with Deciphering Developmental Disorders) recessive disease; contribute to and establish The Human Knockout Project, a worldwide database of population-based studies of human knockouts; perform blood -omics to study major perturbations of biological systems including downstream networks; and deeply study individuals with knockouts and other variants in reported Mendelian disease genes.
Unravelling the intracellular interactions and signalling of Apical membrane antigen-1 (AMA1) in malaria parasites. 24 Apr 2018
Apical membrane antigen-1 (AMA1) is a type-I integral membrane protein of malaria parasites, required for host cell invasion. Invasion requires phosphorylation of the AMA1 cytoplasmic domain (CD), suggesting a signalling role. Exactly what process(es) the AMA1 CD regulates, and how it does so, is unknown. This project will examine the role of the AMA1 CD in regulating cellular events during invasion, using the recently culture-adapted malarial species Plasmodium knowlesi. A conditional mutagenesis system (DiCre) will be used to switch expression of wild-type AMA1 to mutant alleles (e.g. non-phosphorylated forms) to examine the role of the CD in invasion. The impact of mutagenesis on discharge of secretory organelles containing invasion ligands will be examined using immunofluorescence and electron microscopy. Proteins that interact with the AMA1 CD will be identified using directed biotinylation by an APEX2 tag fused to the CD, followed by pulldown and mass spectrometry. The role of interacting proteins in invasion will then be explored using DiCre-mediated knockout. A high-throughput Cas9 mutagenesis screen of the AMA1 CD will also be performed to identify crucial residues involved in mediating interaction of partner proteins with the AMA1 CD. This project will elucidate the long-hypothesised signalling role of AMA1.