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Bacterial immune evasion.
The overall aim of research in my laboratory is to understand the mechanisms by which bacterial pathogens cause disease and to exploit this to design novel approaches for preventing infection. The main questions we will address in this application are: i) what is the basis of host susceptibility to meningococcal disease? A genome wide association study (GWAS) has highlighted that complement facto… more
CON BRIO: Collaborative Network for Bipolar Research to Improve Outcomes.
Bipolar disorder is the sixth leading cause of global disability, but has been neglected and remains poorly understood. We see a unique opportunity to link basic and clinical scientists to establish an inter-disciplinary translational research programme, to transform its understanding and treatment. A key concept, arising from recent work, is that mood instability (rather than episodes of elevat… more
Genetic control of cell fate decisions in the developing mouse embryo.
My previous research has provided fundamental insights into TGFb/Bmp growth signalling pathways controlling axis patterning and cell lineage specification in the developing mouse embryo. A consistent theme emerging from our recent work is that a handful of so-termed master regulators acting downstream of TGFb/Bmp signals govern the transcriptional networks that co-ordinately regulate cell type sp… more
Regulation of intestinal immune homeostasis by NOD-like receptors.
How do innate immune pathways in mammalian hosts determine the level of danger posed by a particular intestinal microbe and respond appropriately? How do innate immune receptors, particularly the inflammasome forming NOD-like receptors (NLR), regulate intestinal homeostasis? How does NLR sensing by intestinal epithelial cells (IEC) contribute to protection and pathology in the intestine? How do d… more
Identification of atypical ubiquitylation and its role in inflammatory signalling.
The overall aim of my research is elucidate key mechanisms governing inflammatory signalling and innate immune responses to invading pathogens. Pathogens are a constant threat to human health, particularly in the gastro-intestinal system. Accordingly, deregulation of inflammatory signalling leads to immunodeficiency, chronic inflammation, and cancer. Uncovering basic mechanisms controlling these … more
Mammalian peptide transporters as targets for advanced drug design and delivery.
My research seeks to develop a mechanistic understanding of peptide and drug transport in the human body via the mammalian PepT1 and PepT2 proteins, members of the proton coupled peptide transporter family of plasma membrane transporters. PepT1 and PepT2 are responsible for the absorption and retention of dietary protein in the form of small peptides and also for the majority of beta-lactam antib… more
Two-pore channels and NAADP-mediated endolysosomal Ca2+ signaling in health and disease.
Stimulus-dependent combinations of multiple Ca2+-mobilizing messengers generate specific spatio-temporal Ca2+ signals which are decoded into distinct cellular responses. Cracking this Ca2+ code requires a detailed understanding of the spatial/temporal choreography of the messengers, proteins and organelles that generate these Ca2+ signatures. The three major messengers regulating Ca2+ signalling … more
Mutations in malformation and disease.
I am interested in the mutational processes that cause malformation and disease, and in relating these to the molecular pathways that are perturbed as a consequence. Using high-throughput sequencing, it is now realistic to obtain an unbiased inventory of mutations relevant to serious human diseases, in a manner that conceptually resembles the saturated mutagen-driven screens undertaken in recent … more
Institutional Strategic Support Fund 2013/14
<p>The ISSF has been renewed for two years (2014-2016) for an additional £3M of funding, and has a remit to:</p> <ol> <li>Assist the Institution in developing its research strategy across Departments and Divisions.</li> <li>Encourage new inter-departmental synergies, cross-disciplinary collaborations, and inter-institutional initiatives.</li> <li>Add value to existing Wellcome Trust investm… more
Open access award 2013/14.
Irish Medical Graduates and the British empire, c. 1870-1920.
The research proposed is designed to establish how, firstly, the British empire defined the education and careers of Irish medical graduates during the period 1870-1920. Secondly, it wishes to find out how these graduates contributed to the British imperial system through medicine and how significant their contribution to that system was relative to their contemporaries from other parts of the Un… more
Drugs and Revolution: Policymaking, Ideology and the Margins of Civil Society in Iran.
The research will encompass the framework of relations among political and social actors with regard to drugs and drug policies, paying attention to the public as well as the private and NGO sectors. It will attempt to describe and define the rationale behind the expansion of civil society organisations working on drug control programmes, in view also of the existing restrictions in other fields … more
Is Commercial Surrogacy Exploitative? A philosophical analysis of the concept of exploitation within commercial surrogacy arrangements, using the industry in India as a case study.
I will expound a unique theory of exploitation. In doing so, I develop an analytic framework that is composed of a sufficient condition for what it is to be exploited, and demonstrate that commercial surrogacy arrangements in India satisfy this condition. This sufficient condition, is preliminarily that, B is exploited by A when B's vulnerability is used by A to take unfair advantage of B. I will… more
Neuronal substrates and functional importance of population dichotomy in the external globus pallidus.
Explaining the necessity and nature of functional diversity and specialization in the brain is a major endeavour of modern neuroscience. Focusing on the external globus pallidus as an exemplar neuronal system to provide a common conceptual and practical line of investigation, and scaling up from molecules to movement, this programme will systemically answer each of these fundamental questions: H… more
Immune recognition by non-catalytic tyrosine phosphorylated receptors.
Leucocyte interactions with their environment are mediated primarily by a large array of structurally diverse cell surface receptors. The members of one large, functionally important subset are phosphorylated on cytoplasmic tyrosine residues upon ligand engagement. We refer to them as Non-catalytic Tyrosine phosphorylated Receptors, or NTRs. A recent survey has identified over a 100 NTRs on huma… more
Protein poly(ADP-ribosyl)ation in genome stability and human disease.
Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription,… more
Medical knowledge traditions at work
To support researchers (excluding the Principal Applicant) who are participating as speakers in the iCHSTM conference at Manchester, July 22-28 2013. The speakers are all part of a panel of which I am joint convenor. The title of the panel is Symposium S056: Medical Knowledge Traditions at Work. Expenses are requested for 8 speakers, whose names, affiliations and paper titles and abstracts have b… more
Large-scale alterations of cortical activity induced by brain lesions and their relevance to behavioural deficits.
My project is concerned with understanding how behaviour is affected after brain damage. To advance current understanding, the work will use a unique converging set of approaches based on (i) analyses of the effects of controlled brain lesions in monkeys, and (ii) computational modelling of remote effects of focal brain injury. In work using animal models, I will induce artificial damage in diffe… more
Eliminating malaria to counter artemisinin resistance.
Artemisinin resistance in falciparum malaria poses the greatest threat to current global initiatives to control and eliminate malaria. Urgent action to contain this threat is needed, but there is no consensus on what containment measures should be undertaken. We propose a multinational clinical and laboratory project to evaluate targeted chemo-elimination (TCE) as a strategy to eliminate artemisi… more