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Implementation of ISARICC's 2018-2022 Strategic Plan
<p>Bridging funds for transition to ISARICC's 2018-2022 Strategic Plan</p>
Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach
Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions. The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whos… more
The role of myelin in experience-dependent white matter plasticity.
The adult brain shows dynamic structural changes with learning and with recovery from damage. Studies in animals are able to characterise such changes with exquisite detail. The vast majority of these studies have focussed on changes occurring in grey matter. We recently provided evidence for learning-related change in the microstructure of white matter pathways of the adult human brain. However,… more
Open access award 2013/14.
Investigation into the role of ADP-ribosyltransferases in DNA repair.
The focus of this proposed project is to better undestand the role of ADP-ribosyltranferases (ARTs) in DNA repair. PARP1 and PARP2 are known to function in the repair of single strand breaks (SSBs), whereas the recently characterised PARP3 facilitates double strand break (DSB) repair via non-homologous end joining (NHEJ). The specific aims of this project are to determine if any redundancy exists… more
The regulation of endo-lysosomal trafficking, growth and exosome biogenesis bydevelopmental signalling cascades.
Late endosomes and lysosomes, intracellular compartments often considered to be sites for macromolecular degradation, have recently been implicated in other fundamental cell biological processes. For example, they regulate growthand biogenesis of secreted vesicles called exosomes, which have postulated roles in development. How these processes and membrane trafficking in endo-lysosomes are linked… more
Directionality and decision making during mitotic exit.
The events that occur during mitotic exit, including chromosome segregation and central spindle formation, are fundamentally different to those that take place at mitotic entry. This asymmetric behaviour ultimately results in cell division rather than simply reverting to the pre-mitotic G2 state. This project intends to define how this asymmetry is generated, initially by identifying the stage at… more
NOD2 mediated mitochondrial fission in bacterial handling and inflammation in Crohn's Disease
<p>NOD2 is the most strongly associated genetic variant for Crohn’s disease in Western populations. owever, little is known about downstream signaling from NOD2, precisely how Crohn’s associated polymorphisms lead to impaired autophagy, defective bacterial handling and antigen presentation, and the consequent inappropri… more
Understanding the inflammatory response of endothelial cells to oxidised low density lipoproteins
<p>Atherosclerosis is a major cause of mortality and morbidity worldwide; it is an inflammatory condition in which lesions are packed with immune cells. One of the key steps in immune cell migration into the vessel wall is activation of overlying endothelial cells. Circulating oxidised low-density lipoprotein (LDL) is a major risk factor for atherosclerosis and a potent activator of endothelial c… more
Characterising and targeting the IL-17/IL-23 inflammatory axis in ankylosing spondylitis and inflammatory bowel disease
<p>Compelling evidence implicates the IL-17/IL-23 inflammatory axis in ankylosing spondylitis (AS),rheumatoid arthritis (RA), as well as inflammatory bowel disease (IBD), with early clinical trials targeting this pathway in AS showing promising results. Central to this axis are innate and adaptive immune cells expressing the ROR-γt transcription factor. Murine studies suggest that small mol… more
Integration of epidemiological and genetic data to reconstruct disease outbreaks in host-viral systems.
The recent history of a virus epidemic can be more accurately reconstructed when genetic and epidemiological data are integrated, compared to focusing on either data type alone. However, current reconstructive approaches are limited, being designed for outbreaks where most cases are identified. We lack a framework capable of powerful inference when more detailed epidemiological and viral genetic … more
Statistical and computational methods for modelling pathogen genetic variation
Bacterial and parasitic genomes exhibit high levels of both diversity and structural variation which make analysis extremely challenging. We focus on P.falciparum, where the standard analysis approach of mapping reads to a reference genome leads to poor characterisations of regions with high sequencediversity or deeply diverged lineages, such as several medically important surface antigen genes. … more
Inducible CRISPR:Cas transcription regulators for de novo assembly of gene regulatory networks
The CRISPR:Cas9 system has proven to be a simple and versatile tool to engineer biology. Initially used for genome editing, CRISPR:Cas9 was rapidly repurposed to carryout programmed transcriptional regulation. The next frontier in expanding its potential will be set off by the design of inducible systems responsive to exogenous cues and/or endogenous metabolites. Leveraging the sensor/actuator ca… more
Analysis of genetic diversity in millions of bacteria using genome graphs
In order to use sequencing to improve public health it is vital to have accurate, flexible, and statistically robust methods for understanding how a new bacterial strain relates to all previously sequenced strains. The underlying goal of this project is to develop a methodsand publicly available tools by which one can rapidly compare any isolate with the pan-genome of all known strains and then s… more
Genetic- and Antigenic Evolution and Phylogeography of EV71 Associated with HFMD in Vietnam over a Three-Year Period 2013-2015 .
EV71 has emerged in Asia as a frequent cause of HFMD. EV71-associated HFMD can be complicated by severe illness including fatal encephalitis. There is no antiviral therapy or vaccine. Understanding the genetic- and antigenic evolution of EV71 is important for understanding the epidemiology of this emerging infection and informing vaccine development, and knowledge of the transmission dynamics is … more
The impact of vaccine platform on the cellular drivers of humoral immunity
<p>The focus of this Fellowship proposal is on how vaccine platform affects the cellular drivers of humoral immunity, specifically memory B cells (mBCs) and T follicular helper (Tfh) cells. I will compare the leading <em>Plasmodium falciparum</em> blood-stage malaria candidate – RH5 – in two vaccine platforms: heterologous viral vectors (chimp adenovirus 63 prime, Modified Vaccinia An… more
The Ethics of Genome Editing in Livestock
<p>Genome editing in livestock (GEL) could potentially be used to mitigate urgent global problems of infectious disease, antimicrobial resistance, global warming, and animal suffering while also increasing agricultural productivity. Despite its imminence and potentially transformative potential, there has been minimal ethical debate about GEL. This project will provide the first in-depth philosop… more
The role of diurnal intracellular chloride changes in cortical network activity and plasticity.
<p>Cyclical changes between sleeping and waking states are a fundamental feature of mammalian physiology. During these different states, our brains exhibit distinct patterns of network activity and different capacities to learn. An understanding of the cellular mechanisms that underlie these processes is important to fully appreciate how daily changes in brain function contribute in health and di… more
A realist review of community engagement with health research
<p>The project will conduct a comprehensive review of community engagement using a realist review approach appropriate for tackling the conceptual complexity and practical diversity of the field. A review team with worldleading expertise in the theory and practice of CE will be supported by an advisory panel of internationally renowned realist review scholars. The review will begin with engagemen… more
Overcoming contraceptive discontinuation by overcoming side-effects: paving the way for personalized contraception in Ethiopia
<p>In the developing world, millions of women discontinue hormonal contraception due to the experience of debilitating physiological side-effects (e.g. excessive and irregular bleeding), yet the causes of these adverse effects is not known. This project will be the first to test the hypothesis that side-effects are caused by unnecessarily high dosage of exogenous hormones in hormonal contraceptiv… more