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Results

The role of β-amyloid in cognition in normal and APP knock-in mice 31 Jan 2017

Working hypothesis: modulation of beta-amyloid (Abeta) production (in the absence of APP overexpression) in mice will lead to changes in brain network activity and cognitive function. Our understanding of dementia pathogenesis has been heavily influenced by the amyloid cascade hypothesis. However, progress is hampered by the fact that (1) little is known about the normal function of Abeta and (2) current mouse models of amyloid pathology rely on over-expression of human APP mutations. APP over-expression alone causes synaptic and cognitive changes that are independent of Abeta production. We propose to examine the role of normal Abeta production in synaptic plasticity and cognition and to characterize a novel knock-in mouse model of amyloid pathology (Saito et al., 2014; the NL-F mouse). We will examine cognitive changes in NL-F mice during aging to establish a profile of brain network changes. We will test the effects of steric hindrance of Abeta production on memory by using an antibody (2B3) that binds across the beta-secretase cleavage site in both NL-F and WT mice. Analysis of memory function will be accompanied by assessment of network activity (c-fos expression), brain metabolite profile (MR-Spectroscopy) and APP cleavage products (using standard biochemical assays) in NL-F and WT mice.

Amount: £31,128
Funder: The Wellcome Trust
Recipient: Cardiff University

Assessing the anticancer properties of Biocyanin SLH 31 May 2018

Haemocyanins are oxygen-carrying proteins found in the haemolymph of molluscs and gastropods. They are of interest to biotech and medical research as strongly immunogenic carrier proteins, for making antibodies to conjugated peptides and for use as cancer vaccines. In addition, direct application of haemocyanin to tumours has been shown to produce an anticancer effect, and haemocyanins from several species including keyhole limpet have shown promise in the treatment of bladder cancer, colon cancer and melanoma. Particularly striking are their lack of toxicity and adverse effects. Recently, Mikota PLC have developed protocols for the purification of a new haemocyanin, Biocyanin SLH, from the slipper limpet Crepidula fornicata. The main aim of our proposal is to test the potential of Biocyanin SLH as an anticancer agent, by incubating it with a panel of cancer cell lines and assessing its ability to induce cell death. In addition, we will investigate the signalling pathways involved in the anticancer action of Biocyanin SLH, determining whether cell death occurs via apoptosis or necrosis, and analysing cellular production of stress molecules. Finally, we will label Biocyanin SLH with a fluorescent dye to track its interaction with cells using confocal microscopy. Keywords: haemocyanin, cancer, cell death.

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

Investigating the relationship between the cerebellum and cognition in both health and disease 30 Sep 2018

The cerebellum is traditionally ascribed only a role in motor coordination. With it containing more neurones than the rest of the central nervous system combined and with connections with almost every other area of the brain concerned with cognition, this seems exceptionally unlikely. Indeed, studies utilising magnetic resonance imaging (MRI) increasingly show strong cerebellar activity associated with cognitive processes. This is still a greatly understudied area with only a few groups researching this. We, therefore, wish to investigate the role of the cerebellum in cognition using large imaging datasets, our own high-field imaging capabilities at Cardiff and various cerebellar-specific MRI processing tools which have not yet been applied to this question. This will allow us to see how well peoples’ cognitive performance in various domains correlates with cerebellar activity and structural differences. Additionally, recent evidence suggests cerebellar structural differences in schizophrenic patients. We wish, therefore, to also investigate if schizophrenia diagnosis and genetic risk for schizophrenia similarly alters cerebellar structure and, if so, at what time during development, if certain cognitive domains are particularly affected and if cerebellar metabolite levels differ in schizophrenic patients compared to non-schizophrenic controls.

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

Influence of Sleep on Human Brain Structure 08 Nov 2017

Sleep is essential to brain functioning and its loss greatly impairs cognition, yet the brain mechanisms underlying the cognitive benefits of sleep remain largely unclear. During sleep, the brain’s functional networks break down, with different brain regions showing decoupled activities. I hypothesize that this decoupling of brain regions will facilitate the remodeling and optimization of brain structural networks, leading to improved brain functioning and cognitive performances after sleep. I will test my hypothesis in human participants by combining measures of brain structure, function, cognition, with brain stimulation during sleep. First, I will study how the structure of inter-regional connections change after sleep, whether these changes improve the network properties, and how these changes are reflected in the function of inter-regional communications. Then, I will study how the post-sleep changes in brain function correlate with brain activity in sleep, and whether these functional changes can be modulated by brain stimulation during sleep. Last, I will study how the post-sleep changes in brain structure differ across different inter-regional connections, and whether these structural changes can predict the selective influences of sleep on different cognitive performances. Overall, this project aims to explore how sleep benefits cognition by improving brain structure for higher functionality.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £81,092
Funder: The Wellcome Trust
Recipient: Cardiff University

Integrative Neuroscience. 14 Jul 2014

Not available

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University

The functions of postsynaptic density implicated in psychiatric disorders in associative memory formation. 10 Feb 2014

Variants in the genes coding for postsynaptic density (PSD) proteins Homer1, DLG1 and DLG2 have been linked to psychopathology and schizophrenia. These proteins are functionally linked to postsynaptic glutamate receptors such asAMPA, NMDA and metabotropic glutamate receptors, and are thought to be key mediators of synaptic plasticity. Since associative learning is dependent on NMDA receptor-mediated synaptic plasticity and is impaired in several psychiatric disorders, we aim to determine the roles that PSD proteins including Homer1, DLG1 and DLG2 have in associative learning, with a view to shedding light on their part in psychiatric pathology To do this, we will a) use in situ hybridization to measure the expression of Homer1 transcription variants, Homer1a and Ania-3, DLG1 and DLG2 during key components of associative learning, including memory consolidation, recall andinhibitory learning, through the fear conditioning of adult rats. b) Use antisense­mediated knockdown of these PSD proteins before consolidation, recall and inhibitory learning, as well as knockout rodent models, to evaluate their function in processes required for associative learning. c) Administer mGiu and AMPA receptor-acting drugs to transgenic animals to investigate gene dependence in associative learning processes.

Amount: £38,873
Funder: The Wellcome Trust
Recipient: Cardiff University

Professional decision making around next generation clinical genetics. 30 Sep 2016

Over the past couple of years new genomic technologies, such as DNA microarrays and high throughout genomic sequencing, have begun to enter clinical practice in a range of conditions. While the promise of such approaches - as heralded by the NHSs 100,000 genomes project - is considerable, the challenges raised by integrating these technologies into the clinic are no less great. To a considerable extent, these challenges centre on professional decision making: these technologies produce large amounts of data, some of which is clinically relevant, some of which is not, but large amounts of which - for example so called VUSs, variants of unknown significance - are uncertain. It is this uncertainty - whether or not a specific stretch of DNA is clinically relevant - and the decision making processes that surround it, that this project will examine. The method used will be ethnographic observation and interviews with laboratory staff, clinical geneticists and other members of the mu ltidisciplinary teams that create, review and interpret this genomic data. While some similar work is taking place in the US, and some UK studies are exploring the impact of this kind of data, particularly around informing patients, there are no current studies focusing on the way professionals generate and interpret this kind of data.

Amount: £145,915
Funder: The Wellcome Trust
Recipient: Cardiff University

Neural correlates of retrieval control in human episodic memory 19 Nov 2014

It is widely assumed that control processes help to extract task-relevant information from episodic memory. Preparatory control processes are thought to facilitate this by influencing the way in which retrieval cues are processed. Neural correlates of preparatory control processes will be obtained by contrasting brain activity elicited by cues directing participants to prepare to retrieve different types of episodic information. Neural correlates of retrieval cue processing will be obtained by c ontrasting brain activity elicited by unstudied items across different episodic memory tasks. The overarching aim of the proposed research is to investigate the extent to which retrieval control processes directly impact upon successful episodic retrieval, thus extending the study of retrieval control from the correlational to the causal. Key goals will include: i) separating EEG correlates of preparatory control processes according to the accuracy of the subsequent memory judgment, then asking whether this neural activity predicts retrieval accuracy, ii) observing whether a resource depletion manipulation decreases both EEG correlates of retrieval control processes and episodic retrieval accuracy, and iii) employing EEG source localisation to identify possible neural generators of retrieval control processes, then targeting these cortical regions with transcranial magnetic stimulation (TMS) and observing the effects on episodic retrieval accuracy.

Amount: £219,932
Funder: The Wellcome Trust
Recipient: Cardiff University

Professional decision making around next generation clinical genetics. 23 Jul 2015

Over the past couple of years new genomic technologies, such as DNA microarrays and high throughout genomic sequencing, have begun to enter clinical practice in a range of conditions. While the promise of such approaches - as heralded by the NHSs 100,000 genomes project - is considerable, the challenges raised by integrating these technologies into the clinic are no less great. To a considerable extent, these challenges centre on professional decision making: these technologies produce large amounts of data, some of which is clinically relevant, some of which is not, but large amounts of which - for example so called VUSs, variants of unknown significance - are uncertain. It is this uncertainty - whether or not a specific stretch of DNA is clinically relevant - and the decision making processes that surround it, that this project will examine. The method used will be ethnographic observation and interviews with laboratory staff, clinical geneticists and other members of the mu ltidisciplinary teams that create, review and interpret this genomic data. While some similar work is taking place in the US, and some UK studies are exploring the impact of this kind of data, particularly around informing patients, there are no current studies focusing on the way professionals generate and interpret this kind of data.

Amount: £232,876
Funder: The Wellcome Trust
Recipient: Cardiff University

Conjugated Polymeric-Based Prodrug to enhance steroidal delivery into cartilages 25 Aug 2015

Osteoarthritis (OA) is the key disease focus of the project, mainly through an improvement of the currently available drugs uptake. Additionally, a more selective distribution of the drug in the cartilage will reduce the required dose; both factors contributing to a reduction of the side effects associated with the drugs. The prevalence rate for OA is 11.3% or approximately 85 million people globally. It is expected to increase from 85 million in 2009 to 122 million in 2017. The main reason for this is the high incidence rate in the elderly population and the aging population trend. In addition, a rapid increase in the obese population will also contribute to an increase of the incidence of OA.

Amount: £73,028
Funder: The Wellcome Trust
Recipient: Cardiff University

Cardiff, Integrative Neuroscience. 29 May 2015

Not available

Amount: £150,321
Funder: The Wellcome Trust
Recipient: Cardiff University

Investigating the dysregulation of gene expression in 22q11.2 deletion syndrome with human IPS and ES cells and its link to schizophrenia 30 Jan 2015

We hypothesise that 22q11.2 deletion syndrome (22q11.2DS) has an increased risk to schizophrenia and Parkinsons disease (PD) due to abnormal dopaminergic(DA) neuronal development and/or function, which is the consequence of a global dysregulation of gene expression triggered by the haploinsufficiency ofDGCR8. We will perform a comprehensive analysis of the phenotypes of DA and MSN neurons derived from 22q11.2DS induced pluripotent stem cells (iPSC), DGCR8 knock-out human embryonic stem cells (ESC), and if time permit, 22q11.2DS iPSCs overexpressing transgenic DGCR8. Moreover, we will seek further support that DGCR8 has a primary role in 22q11.2DS by analysing the dopaminergic neuron system of DGCR8 conditional knockout mice. This will provide us a unique understanding of the abnormalities caused by thedeletion and by cross-referencing our results and previous genomic studies this study will provide valuable insight to how these deficits may confer riskto schizophrenia and PD.

Amount: £34,290
Funder: The Wellcome Trust
Recipient: Cardiff University
Amount: £118,478
Funder: The Wellcome Trust
Recipient: Cardiff University

Integrative Neuroscience 30 Sep 2016

Not available

Amount: £118,478
Funder: The Wellcome Trust
Recipient: Cardiff University

The Phenotypic Expression of Neuropsychiatric Copy Number Variants 02 Mar 2016

Copy number variants (CNVs) are associated with neuropsychiatric disorders across diagnostic boundaries. The phenotypes associated with most neuropsychiatric CNVs are poorly defined. The aims of this project are to identify CNV carriers and establish the psychiatric, cognitive and neurodevelopmental phenotypes associated with neuropsychiatric CNVs. Two approaches will be used: (i) examining neurocognitive phenotypes of CNV carriers in the largest available population sample (Biobank UK), (ii) recalling CNV-carrying individuals from psychiatric genetic datasets and characterising their psychiatric, cognitive and neurodevelopmental phenotypes. I hypothesise that CNV-carrying individuals will display more frequent and severe impairments than those without CNVs. The first stage of the project will involve calling CNVs in 500,000 individuals (Biobank UK). I will analyse these data for associations between individual CNV loci and phenotypic domains tapping mental health, cognitive functioning and neurodevelopment. In the second stage, I will develop expertise in deep phenotyping by recalling and investigating individuals with psychiatric disorders and CNVs and comparing to those with equivalent psychiatric disorders without CNVs. Participants will undergo comprehensive assessment including psychiatric (SCAN) interview, Autism Quotient questionnaire, CANTAB Schizophrenia Cognitive Battery, developmental history, examination for soft neurological signs (Neurological Evaluation Scale) and dysmorphology assessment with clinical photography (adapted Waldrop Scale).

Amount: £193,209
Funder: The Wellcome Trust
Recipient: Cardiff University

Protocadherin 19 in cortical development. 16 Sep 2015

Mutations in Pcdh19, a delta-2 protocadherin encoded on the X chromosome, lead to epilepsy with cognitive impairment in heterozygous females. The early disease onset suggests a neurodevelopmental basis for the disorder, but the function of this gene is entirely unknown. We propose to use the developing mouse brain to analyze early roles of Pcdh19 in neurogenesis, migration and circuit formation. Data from expression studies, anatomical analyses and the unusual inheritance mode of the disorder, w ith unaffected hemizygous males, support a role of Pcdh19 in these processes. We will first perform a comprehensive molecular and hodological characterization of Pcdh19 expressing cells at different developmental stages. We will then analyze a Pcdh19 null mouse mutant and assess whether neurogenesis and/or migration are affected. Using in utero electroporation, we will directly interfere with Pcdh19 function, either by shRNA to cause an acute reduction of its levels or with mutant forms of the p rotein. Synapse analysis in embryonic stem cell-derived neurons and electrophysiological recordings in brain slices will complete the analysis. Our results will provide insight into the roles of Pcdh19 during corticogenesis and form a useful basis for subsequent studies.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Non-Invasive Blood Glucose Meters 30 Sep 2015

Diabetes is affecting hundreds of millions of people worldwide who have to monitor their condition using invasive methods (e.g. pricking of finger or insertion of needle into hip region). It is clear that non-invasive, continuous monitoring has the potential to help and encourage patients to monitor their diabetes more closely due to the associated improved quality of life. This incentive will lead to a reduction of hyper/hypoglycaemic episodes and the subsequent reduction of long-term risks, such as morbidity and shorter life expectancy, when this condition is poorly monitored and managed. The Trust has awarded a team, led by Professor Adrian Porch from University of Cardiff, £892k to develop a non-invasive blood glucose monitor (NIBGM). Their device will improve the quality of life of people with diabetes and, with better management of their condition encouraged by the device, improve their life expectancy. It is fundamentally different from all other glucose monitoring systems on the market in that it does not require blood to be extracted from the patient, or for the sensing element to be inserted into the patient’s body. It is merely attached to the person’s hip with adhesive, does not require blood extraction, and provides an instant readout of the blood glucose level on a unit that can be carried in the person’s pocket. The underlying technology for the device is based on microwaves and how they interact with the person’s blood. However, there is no heating (the microwave field strength is much smaller than that generated by a mobile phone) and the only sensation is that of touch. It is envisaged that final device will be around the size of a £2 coin and will be ready for mass-manufacture.

Amount: £97,900
Funder: The Wellcome Trust
Recipient: Cardiff University

Neuroimaging of functional plasticity in multiple sclerosis. 24 Jun 2013

The aim of this PhD is to determine the disease modifying effect of exercise interventions for Multiple Sclerosis (MS) patients. Aerobic exercise has been shown to slow neurological disease progression and symptom severity in animal models and cross-sectionally in human. Limited intervention data exists and understanding of the relationship between aerobic fitness, MS symptoms and brain structural and functional characteristics is limited. For the main experiment, 30 patients will undergo structural and functional magnetic resonance imaging (MRI) during rest, a CO2 challenge and cognitive tests to assess memory and reaction time. Using MRI techniques we will measure the brain changes following a structured exercise intervention. The key outcome measures will be changes in fitness (VO2 peak), balance, cerebral blood flow (CBF), cerebral blood volume (CBV), grey matter volume (GMV) and white matter microstructural changes assessed using diffusion weighted imaging (DWI). This research add to knowledge of the mechanisms of exercise-related neuroprotection by combining CBF and structuralmeasures before and after an exercise intervention.

Amount: £149,673
Funder: The Wellcome Trust
Recipient: Cardiff University

Visualising pathways for learning in the rodent brain 11 Feb 2013

Two complementary approaches will be developed and refined to examine and compare the properties of neural systems that support different forms of learning. The first approach will use twin fluorescent-tagged markers in the same rodent brain: One marker to reveal neurons that show selective increases of activity (e.g., by using the expression of immediate-early genes such as c-fos as proxy markers for learning-related activity), the other marker to determine the connectivity of the same neurons by the use of retrograde fluorescent markers. The goal is to isolate putative pathways in the brain for particular forms of memory, and then to test the specificity and nature of their involvement. Attention will focus on spatial memory and recognition memory. The second approach will test the temporary knock down of anatomically specified pathways, e.g., using the Daun02 inactivation technique. This approach makes it possible to examine the causal roles of anatomically isolated systems. This research will again compare spatial memory with recognition memory, where appropriate behavioural protocols have been developed in the host laboratory.

Amount: £30,066
Funder: The Wellcome Trust
Recipient: Cardiff University