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Results

ROS via RET: a redox regulated pathway to extend lifespan 17 Jul 2018

Reactive Oxygen Species (ROS) play a dual role in cellular physiology. On one hand, ROS are damaging oxidants that have been proposed to cause ageing. On the other, ROS are essential messengers required for maintaining cellular homeostasis. The aged and sick accumulate defective mitochondria that generate high levels of ROS, but antioxidant therapies fail to improve prognosis or extend lifespan. Furthermore, increasing mitochondrial ROS levels in animals extends lifespan rather than reducing it. A new paradigm explains these contradictory results proposing that under normal physiological conditions, ROS are only produced at specific sites (e.g. mitochondria) by specific ROS generators (e.g. respiratory complex I) which regulate distinct redox signalling pathways. Conversely under pathological conditions ROS are produced at unspecific places causing oxidative stress. My laboratory has characterized the first site-specific ROS signalling pathway which regulates animal lifespan: ROS produced via reverse electron transport (RET) at respiratory complex I. This proposal will fully characterize this new redox signalling pathway by addressing three aims: (i) identify the genes and proteins involved in the initiation, amplification and neutralization of ROS-RET, (ii) understand when and where ROS-RET needs to be activated to extend lifespan, and (iii) dissect the pathological consequences of dysregulation of ROS-RET signalling.

Amount: £1,512,586
Funder: The Wellcome Trust
Recipient: Newcastle University

EpiChange: Quantifying longitudinal changes after epilepsy surgery 04 Dec 2017

Resective surgery for epilepsy, where the part of the brain thought to cause seizures is removed, leads to seizure freedom in around 70% of patients 1 year post-surgery. This falls to around 50% at 5 years post-surgery. It is not fully understood why surgery only works initially for some patients, and why this falls over time post-operatively. Surgery has a substantial immediate impact on brain structure, however, the long-term impact of surgery on brain dynamics is poorly understood. In order to make progress in this area we will perform a retrospective analysis of longitudinally acquired electroencephalographic (EEG) data. EEG recordings were made pre-operatively, and post-operatively in 76 patients for up to 5 years. Using univariate and multivariate data analysis, in conjunction with machine learning, we will learn how brain dynamics change after surgery, and if this change relates to outcome. Crucially, we will attempt to identify which factors in brain dynamics correlate with seizure relapse, even years after surgery. If successful, this will pave the way to a larger project where changes can be reverse engineered to give predictions of post-operative decline using pre-operative data. Long-term, this research has implications for other disorders involving longitudinal decline following structural brain damage.

Amount: £99,978
Funder: The Wellcome Trust
Recipient: Newcastle University

MA in History of Medicine 11 Jul 2018

The Master of Arts in History of Medicine at Newcastle combines three modules common to all MA History programmes with three bespoke modules that deepen students’ understandings of medical history and develop their methodological and historiographical skills, in preparation for their dissertation. ‘Introduction to the History of Medicine’ provides an overview from antiquity to the twenty-first century, analysing the relationship between medicine and other aspects of Western and non-Western human civilizations; ‘The Patient in History’ examines how patients have been perceived, constructed and contested, and considers the extent to which the patient’s voice can be retrieved from different source materials; ‘Diseases in History’ analyses how diseases have been socially, culturally and historically understood, constructed and responded to. The core history modules are ‘The Practice of History’, which studies how historians have practiced their discipline in the second half of the twentieth century; ‘Research Skills and Dissertation Training’, which equips students with the practical skills required for dissertation work; and the 60 credit Dissertation module. Students select the independent study module, or a further MA module from within the Faculty of Humanities and Social Sciences. Assessment methods include research essays, a literature review, a poster, a dissertation proposal and the dissertation.

Amount: £78,132
Funder: The Wellcome Trust
Recipient: Newcastle University

Innate lymphoid cells; promoting homeostasis and preventing gut dysbiosis 09 Nov 2016

I propose to examine the hypothesis that innate lymphoid cells (ILCs) mediate crosstalk between the intestinal microbiota and the reconstituting adaptive immune system in a cohort of children with primary immunodeficiency disorders undergoing haematopoietic stem cell transplantation (HSCT). I will use mass cytometry to examine the reconstitution of leukocyte populations after HSCT in a longitudinal fashion. I will characterise the peripheral blood ILC compartment in detail, including expression of activation markers, chemokine receptors and cytokines by ILC subsets ex vivo. I will measure gut bacterial diversity in longitudinally collected faecal samples and assess markers of microbial translocation. These immune and microbial parameters will be correlated with clinical features in a multi-dimensional statistical model to identify risk factors for HSCT outcomes such as graft-versus-host disease (GVHD) and gut failure. Further analysis of ILC function will be performed through in vitro studies of these immune populations to examine how they can regulate T cell responses. The impact of microbial signals and cytokines on ILC regulation of T cells will be assessed. A better understanding of ILC function in the context of immunodeficiency and HSCT may help us to develop strategies to avoid immune complications such as GVHD in some transplant recipients.

Amount: £353,977
Funder: The Wellcome Trust
Recipient: Newcastle University

Mapping the genetic and cellular basis of human DC haematopoiesis. 15 May 2017

Hypothesis: Human DC haematopoiesis is regulated by specific genetic factors that govern the development of precursors with restricted DC potential, giving rise to peripheral DCs independently of monocytes. Objectives: 1.To identify genes of clinical importance regulating human DC haematopoiesis in vivo. I have shown that DC deficiency syndromes provide a powerful means of analysing the genetic factors that control DC development in vivo. I will further screen and characterise new genetic causes of DC deficiency. 2.To identify human progenitors and precursors with restricted DC potential. DC precursors identified in the mouse have no known human homologues. I aim to solve this problem using transcriptomic profiling to identify and separate precursors with true DC potential from those with monocyte potential (that subsequently form mo-DCs), comparative transcriptomics to discover new cross-species markers of DC precursors and single cell progenitor studies to track monocyte- independent DC potential. 3.To define the intrinsic effects of genetic mutation on discrete stages of DC development. I will use CD34+ progenitors or induced progenitor stem cells from patients with DC deficiency to determine how genetic mutation interrupts discrete stages in DC development, thus integrating the genetic and cellular maps of DC homeostasis.

Amount: £216,055
Funder: The Wellcome Trust
Recipient: Newcastle University

The impact of patient mutations in Na/phosphate cotransporters to function and trafficking of the protein 31 May 2018

The renal transport system for inorganic phosphate (Pi), SLC34A1, is central to balancing Pi levels in the human body. Mutations in SLC34A1 have been identified in patients with isolated renal phosphate wasting, generalised proximal tubulopathies (renal Fanconi’s syndrome), renal stone formers and patients with nephrocalcinosis. The spectrum of phenotypes observed points to a complex interplay between the nature of the mutation and the genetic background of the patient. Intriguingly, some of the mutations show a dominant phenotype. The aim of this proposal is to investigate the molecular and cellular determinants for the dominant behaviour of certain SLC34A1 mutations. We have identified two patients with mutations in SLC34A1. The first patient carries a heterozygous SLC34A1 mutation Ile456Gln whilst the second is compound heterozygous for Arg512Cys and a deletion of Val91-Ala97. These mutations will be used to perform functional analyses in Xenopus oocytes and epithelial cell lines co-expressing wild-type and mutated transporters. Chimeric wt-mutant constructs will also be generated to exclude differences in intracellular processing of the individual units. Intracellular trafficking will be tested in renal epithelial cell lines using wild-type and mutated transporters with different fluorescent tags followed by confocal microscopy.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Expression profiling of p53 transcriptional target genes as a predictor of cell fate following non-genotoxic activation of p53 by MDM2 inhibitors 31 May 2018

The purpose of the proposed project is to investigate the differences in p53-dependent gene expression between cells that undergo growth inhibition and senescence in response to p53 activation compared with those that undergo apoptosis. These alternative cell fates, which are cell type and context dependent, have important roles in a range of disease states and responses to therapeutic intervention, but the underlying mechanisms are poorly understood. We have identified a panel of cell lines that epitomise these alternative cell fate responses to p53 activation, which we will investigate by using MDM2-p53 binding antagonists to activate p53 directly and specifically, without DNA damage. In addition, we will use agents which demethylate DNA to test whether pro-apoptotic genes can be re-activated in those cell lines in which these genes appear to be silenced. Techniques used to investigate the downstream consequences of p53 activation will include flow cytometry, enzymatic apoptosis and senescence assays, Western immunoblotting and multiplex qRT-PCR gene expression profiling.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Vacation Scholarships 2018 - Newcastle University 16 Jul 2018

Vacation Scholarships 2018 - Newcastle University

Amount: £18,500
Funder: The Wellcome Trust
Recipient: Newcastle University

An Extended Pilot for the Human Cell Atlas: Adult tissues, human development and inflammation-mediated pathologies 30 Sep 2018

The Human Cell Atlas (HCA) is an international, collaborative effort that "...aims to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location". Here, we will contribute directly to the first phase of the HCA by forming an ‘extended pilot’ to implement UK infrastructure for large-scale, high quality human cell atlas experiments. We will generate a high-level atlas, with spatial resolution, for multiple adult human tissues along with matched data from human fetal material. We will then illustrate the power of a deep and focused investigation of a single tissue (skin) to produce highly-detailed data describing its cellular composition and spatial organisation. Finally, for selected tissues that have been profiled in adults and fetal material, we will analyse samples from immune-mediated disorders as a comparison with our reference data to gain deeper understanding of the pathological mechanisms. This will demonstrate the utility of the HCA as a ‘healthy reference’ for comparison with disease. Throughout, we will generate profound biological insight from primary human cells and lay a foundation of technology development and optimisation with a set of hardened and scalable methods for single-cell RNA-sequencing, spatially-resolved gene expression, and tissue imaging.

Amount: £849,370
Funder: The Wellcome Trust
Recipient: Newcastle University

Bases for auditory cognition. 01 Apr 2015

Auditory cognition is the mechanism for making sense of the acoustic world. This is a necessary basis for the understanding of speech, environmental sounds and music that interacts with common hearing loss and is affected by common brain disorders. The work extends my approach to auditory cognition using synthetic stimuli that are statistically similar to natural stimuli. The work addresses two critical and broad systems for auditory cognition: auditory figure-ground analysis and working memory. The two human systems would be defined by modelling neurophysiological data acquired non-invasively (magnetoencephalography) and invasively (neurophysiology on neurosurgical subjects). Pilot work suggests systems for auditory figure-ground analysis involving auditory and parietal cortex and for working memory involving auditory cortex, frontal cortex and hippocampus. In particular, the work tests whether these systems obey the principle of predictive coding with prominent backward connectivity from high-level areas to auditory cortex. My previous work on perception supports this idea, but application of predictive coding to auditory cognition in general is controversial. Human clinical work would establish how these two systems contribute to speech-in-noise detection deficits in cochlear hearing loss and how common brain disorders affect the two systems.

Amount: £1,718,617
Funder: The Wellcome Trust
Recipient: Newcastle University

Cyclin B1, critical regulator of the timing of cell division. 14 Apr 2014

A critical aspect of the cell cycle is the maintenance of high levels of cyclin B1 at metaphase followed by its rapid APC driven destruction as chromosomes segregate. Impaired regulation of cyclin B1 at this stage of the cell cycle is firmly associated with aneuploidy. Knowledge of cyclin B1 control is largely limited to studies in mitotic cells. Here I will address for the first time whether mechanisms differ between mitosis and meiosis. Indeed preliminary data provide strong evidence to sugges t vastly differing regulation and have therefore led to the design of experiments to fully characterise this. Specifically; to determine how cyclin B1 is recognised by the meiotic destruction machinery and to detail the mechanistic implications of differential spatial control of both cyclin B1 and the APC in meiosis and mitosis. Differential cyclin B1 control mechanisms ultimately point towards the existence of meiosis specific APC activator. A key goal of this project will be to uncover its identity and detail a role in both vertebrate and invertebrate meiosis. A full understanding of the physiological process which regulate cyclin B1 and metaphase exit is important since errors are not uncommon and have a great negative impact on human health.

Amount: £104,041
Funder: The Wellcome Trust
Recipient: Newcastle University

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £140,000
Funder: The Wellcome Trust
Recipient: Newcastle University

Sex-dependent gene regulation in immune cells 29 Nov 2016

Sex is a fundamental but frequently overlooked biological characteristic of humans and model organisms that affects immune responses. I aim to develop integrative bioinformatics approaches to interrogate publicly available transcriptomics and epigenomics datasets to delineate the sex-determined molecular mechanisms that modulate the immune system. My group will generate models of the sex- and cell-specific gene regulatory networks for the major blood cell types where data is available. We will study how these sex-specific networks derived from healthy cells are influenced by infections and other disease conditions. We will develop new bioinformatics tools to integrate the sex-specific transcriptional programs with diverse sources of epigenomics information to identify the distinct chromatin configurations that underlie the different immune responses in men and women. These results will provide the necessary framework to understand the molecular differences in men and women in response to infections, autoimmune disease and in immunodeficiencies. This will provide new insights underlying disease pathogenesis and facilitate personalized therapy for men and women.

Amount: £78,166
Funder: The Wellcome Trust
Recipient: Newcastle University

The role of protein kinases in the regulation of Rif1 during DNA damage and spindle damage in eukaryotic cells 27 Apr 2017

Rif1 (Rap1-Interacting Factor 1) protein is a well-conserved DNA-damage-response factor, required for cell survival after DNA damage and for proper execution of DNA replication. Little is known about how does Rif1 achieve these functions or how it is regulated. This project will investigate potential roles for certain protein kinases, in phosphorylating Rif1 in response to telomere and spindle damage. The protein kinases will be selected from a list of factors demonstrated to interact with Rif1 in high throughput assays. The key goal is to Identify the protein(s) phosphorylating Rif1, which may help us understand the mechanisms by which telomere dysfunction is involved in carcinogenesis.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

DNA repair status and drug sensitivity of a novel patient derived cell line 27 Apr 2017

In this project I will measure the expression of various proteins involved in the DNA damage response (DDR) in extracts of a novel cell line that spontaneously immortalised from a primary culture of ascites cells from a patient with clear cell ovarian cancer. I will also determine the sensitivity of this cell line to DNA damaging anticancer drugs and ionising radiation, potentially also in combination with inhibitors of the DDR, e.g., ATR, PARP, using both growth inhibition and cytotoxicity assays. If time allows, I will also measure cell cycle perturbations after DNA damage. At the end of the project I will compare the cytotoxicity data with the protein expression data (and potentially the cell cycle analysis) to determine if expression levels of DDR proteins can be related to sensitivity.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

How early visual cortex encodes the binocular statistics of the natural world 30 Sep 2017

Stereoscopic “3D” depth perception relies on sensing small disparities between the images viewed by the left and right eyes. Comparing the two eyes’ images and extracting these disparities is a complex process which begins in the brain’s primary visual cortex (V1). Many neurons in this cortical area are sensitive to binocular disparity, even when no other depth cues are present. I want to understand how they achieve this. Current neural network models capture many aspects of this computation, but real neurons seem better adapted to the statistics of the real world than current models can explain. I plan to record from individual neurons in the primary visual cortex as many thousands of stereoscopic images are viewed. I will exploit new analytical techniques to fit more sophisticated models. I will explore how current models fail, e.g. by failing to capture how real neurons respond to differences in contrast and spatial frequency. I will then modify current models, e.g. by incorporating divisive normalisation. I hope this will produce new insights into how the two eyes’ images are combined in the brain, with benefits to other aspects of perception.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: Newcastle University

An ethical discussion of in-vitro meat and the production of flesh from animals with enhanced properties. 10 Feb 2014

The creation of 'synthetic meat' and animals with enhanced properties, such as reduced sentience and nutritional benefits, may reduce a number of animal welfare and human health concerns whilst raising other issues, including questions related to the dignity of animals and the naturalness or otherwise of these developments. New concerns associated with these novel technologies are not easily understood in terms of conventional bioethical concerns that focus on welfare. The ethical and social ben efits of these new and proposed scientific developments must be addressed by those with an interest in the ethical issues associated with the consumption of animal products. This workshop will provide a unique opportunity to bring together a number of experts on these issues with the aim to develop a better understanding of the issues involved. This understanding can then form the basis of future work, resulting in the creation of detailed research projects that will be submitted to appropriate funders, and publications. This workshop is very timely. The recent creation of the worlds first in vitro burger intersects academic debate in various ethical disciplines, including conventional bioethics, animal ethics, and public health.

Amount: £4,771
Funder: The Wellcome Trust
Recipient: Newcastle University

Technologies of identification and responses to mass death: a PEALS symposium on the social and ethical aspects of DVI. 10 Feb 2014

The requested funding will part-support up to 6 international speakers to attend the 15th annual PEALS international symposium on Technologies of identification and responses to mass death in April 2014. PEALS symposia traditionally assemble a small number of invited discussants representing a range of experts, affected communities, practitioners and policy makers, for 2 days of exchange and dialogue. Objectives for the 15th symposium are: (i) to outline key social and bioethical questions r aised by the application of biomedical technologies in disaster victim identification (DVI); (ii) to examine how differently involved groups develop, respond to, and evaluate DVI practices; (iii) to enable a range of perspectives to inform the discussion by convening leading figures from academia, practice and policy with experience in the design and execution of DVI efforts, with input from representatives of affected communities; (iv) to compare and contrast the social and bioethical issues presented by DVI efforts in differing settings including military conflict, terrorist attacks, and natural disasters; (v) to facilitate future cooperation between involved groups; (vi) to identify areas for future social and bioethical research.

Amount: £4,250
Funder: The Wellcome Trust
Recipient: Newcastle University

Mapping the genetic and cellular basis of human DC haematopoiesis. 21 May 2013

Hypothesis: Human DC haematopoiesis is regulated by specific genetic factors that govern the development of precursors with restricted DC potential, giving rise to peripheral DCs independently of monocytes. Objectives: 1.To identify genes of clinical importance regulating human DC haematopoiesis in vivo. I have shown that DC deficiency syndromes provide a powerful means of analysing the genetic factors that control DC development in vivo. I will further screen and characterise new genetic causes of DC deficiency. 2.To identify human progenitors and precursors with restricted DC potential. DC precursors identified in the mouse have no known human homologues. I aim to solve this problem using transcriptomic profiling to identify and separate precursors with true DC potential from those with monocyte potential (that subsequently form mo-DCs), comparative transcriptomics to discover new cross-species markers of DC precursors and single cell progenitor studies to track monocyte- independent DC potential. 3.To define the intrinsic effects of genetic mutation on discrete stages of DC development. I will use CD34+ progenitors or induced progenitor stem cells from patients with DC deficiency to determine how genetic mutation interrupts discrete stages in DC development, thus integrating the genetic and cellular maps of DC homeostasis.

Amount: £964,788
Funder: The Wellcome Trust
Recipient: Newcastle University

A model for cortical analysis of auditory-objects. 15 Jul 2013

I aim to define auditory-object analysis at the systems and neuronal level. I will use a systematic approach based on 'stochastic' stimuli that are equally relevant to animal and human perception. Project 1 will determine whether the perception of a spectral flux stimulus (PMID: 19052218) is similar in animals and humans. Recent work by my group has demonstrated similar perceptual pitch boundaries in animals and humans [doi:10.3389/fpsyg.2014.00998]. I will use similar psychophysical paradigms to establish spectral flux discrimination and compare performance with human data. Project 2 uses fMRI to define the network for spectral-flux analysis compared to the known physiological areas in the same three subjects. Specifically, I would test the hypothesis (based on my M.Res work) that the representations of spectral flux are fundamentally different in core and belt/parabelt areas, and define systems based on the analysis of effective connectivity with Granger Causality and Dynamic Causal Modelling. Finally, in Project 3 I would record LFPs and and single-unit responses from core and belt areas identified in the fMRI work to establish neuronal bases for spectral flux analysis.

Amount: £152,533
Funder: The Wellcome Trust
Recipient: Newcastle University