Download Research Funding Scheme 2005 (1st Call) - Awarded

NISCHR PhD Studentships – 2007/2008
Project Title
Grant
Lead Researcher
Institution
ARREST-Action Research to Reduce Repetition of Stroke
£48,848
Dr Susan Lambert
Swansea University
Welsh individuals with diabetes are advised to take regular exercise as part of a healthy lifestyle. However, patients face an increased risk of
hypoglycaemia during and after exercise which may predispose those individuals to syncope, coma or even death. Strategies to prevent exerciseinduced hypoglycaemia in patients with Type 1 diabetes mellitus (T1DM) are unclear. Providing definitive advice on insulin therapy and feeding
strategies prior to exercise participation is complex, in part due to the interactions of different insulin preparations, different doses, food intake and
timing of administration prior to exercise. With local research ethics approval, patients with T1DM will be recruited for a series of experiments
examining the impact of; (i) reductions in the dosage of insulin prior to performing aerobic exercise; (ii) changes in the type of ingested
carbohydrate prior to performing a bout of exercise and (iii) alterations in the timing of insulin administration and carbohydrate feeding on the postexercise glucose concentrations. Patient’s ventilatory responses will be measured during exercise and the amount of glucose oxidised will be
calculated. Blood samples will also be taken before and after exercise to determine the glucose (and other metabolite) changes post-exercise. With
the increasing number of young type 2 patients and the aim for tight glycaemic control and hence increased use of insulin, the results from this
study would be applicable to a significant proportion of the 5% of the Wales population who have diabetes (Welsh Health Service report 2002).
Therefore, controlled studies on the effects of the above-mentioned factors on T1DM patients undergoing physical exercise is warranted. The study
will generate information on avoiding the occurrence of hypoglycaemia (secondary prevention) and avoiding or delaying complications (tertiary
prevention) associated with long term hyperglycaemia.
Commitment and potential of dental pulp cells: their role in directing
dental tissue regeneration
£70,000
Dr Alastair J Sloan
Cardiff University
Dental decay continues to be the most prevalent infectious disease in the world, affecting 80% of adults. In England and Wales, dentists place 20
million restorations due to recurrent decay each year at a cost of £173 million. Replacement of failing restorations accounts for 80% of clinical work.
If untreated, infection progresses to the central pulp (nerve) of the tooth
affecting general health, reducing quality of life. Dental infection is the commonest reason for lost working days and continued infection leads to
dental abscess formation outside the tooth, where systemic migration of bacteria has been linked with heart and blood infections. A future ageing
population will compound these problems.
The dental pulp contains several populations of potential immature / progenitor cells. One population is associated with the blood vessels and we
have recently isolated two further immature cell populations from dental pulp of developing tooth and embryonic tissue origin. These cells are likely
to play key roles in the repair process, able to mature into dental tissue (dentine)
forming cells (odontoblasts) and lay down reparative dentine at the dentinepulp interface to regenerate lost tissue. Importantly, this reparative
dentine is atubular (unlike dentine of the first-formed tooth) thus providing a natural barrier to bacteria leaching from around a restoration.
A therapeutic approach to improving longevity of dental restorations is to develop novel restorative materials so that they attract the immature cells
to a site below the restoration and stimulate tissue regeneration. To develop this approach we need to understand the responses of these immature
cells to their natural micro-environments and current restorative materials. We have demonstrated that existing dental materials are capable of
stimulating reparative dentine formation by encouraging the release of bioactive molecules from surrounding dentine. Such molecules could be
harnessed and manipulated encouraging immature cells to form reparative dentine.
Novel Behavioural & Molecular determinants & Indicators of attention
deficit/hyperactivity disorder in adults
£59,000
Dr Andrew N Coogan
Swansea University
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition in children, with an incidence of between 3% and 9%. ADHD is
characterised by attention difficulties, impulsivity and motor hyperactivity. Sleep problems are also found to be common in ADHD children. A
significant number of affected children will carry over symptoms into adult life, with those suffering from adult ADHD exhibiting emotional problems
and an increased risk for secondary problems such as emotional instability, drug addiction and delinquency. ADHD in adults is also associated with
sleep problems, and this impairment of sleep may contribute to the symptoms of ADHD in adults and children. This project will address how this
sleep disturbance may come about in ADHD, and reveal insights into how ADHD in adults may be better managed.
The regulation of sleep is a deeply complex process, with many factors in play. One of the physiological systems that is known to play a vital role in
determining our sleep patterns is the circadian clock. Circadian rhythms are recurring patterns in behaviour and physiology that repeat
approximately every twenty four hours (the term circadian means about a day). The body’s circadian clock is known to provide a major impetus to
sleep onset and maintenance, and sleep disorders have been associated with mutations in “clock” genes, responsible for the generation of circadian
rhythms. Further, mutations in clock genes have also been implicated in a number of psychiatric conditions, such as bipolar disorder, and recent
work from the applicants have shown a mutation in a clock gene is associated with ADHD in adults. We wish to build on these findings, and examine
the circadian clocks of adults with clinically defined ADHD, so that we can better devise appropriate behavioural and pharmacological interventions.
The effect of ethnicity upon willingness to care and patient/carer quality
of life
£61,263
Dr Val Morrison
Bangor University
Government statistics show that the Asian population is growing in Wales with 26,000 Asian people living in Wales in 2001. The Asian population is
the largest ethnic minority group in the country yet there has been little research into the British Asian caregiver. This group may be particularly
vulnerable to stress due to low social economic status, language barriers and low perceptions of social support; all factors that have been associated
with poor coping and negative outcomes when using Caucasian caregiver samples. There is to date a limited body of evidence regarding the
influences upon, and outcomes of caregiving, amongst Asian caregivers.
This PhD proposal builds upon pilot survey work conducted as part of the applicant’s Masters degree which explored Asian caregivers willingness to
provide family care in the context of disabling disease. This larger scale research would enable a series of studies using mixed methodologies to
explore factors associated with willingness to care and subsequent caregiver quality of life. The proposed studies are designed to advance
understanding of the ethnic variations in the caregiver experience as ultimately this should enable practitioners and service providers to meet the
needs of the caregivers they serve. By highlighting any similarities and differences between the ethnic groups studied, the theoretical understanding
of caregiver experience can be extended and practical implications for care provision can be drawn. The particular focus of the proposed programme
owork is that of familism- a term which describes individuals attitudes towards family and family values. I will explore whether familism influences
willingness to provide care and the quality of life experienced over time by those providing care in a range of illnesses.
The role of AGE - RAGE signalling on transcriptional activity in normal
and Poly-Cystic Ovary Syndrome Human Endometrium
£67,000
Dr Steve Conlan
Swansea University
Polycystic ovary syndrome (PCOS) is a common and heterogeneous reproductive endocrine disorder that affects 4–6% of premenopausal women. Its
etiology is unknown and it is diagnosed by the presence of hyperandrogenism and chronic anovulation with the exclusion of the adrenal, ovary and
pituitary disorders. PCOS is also characterized by several metabolic aberrations, including high incidence of impaired glucose tolerance,
hyperinsulinaemia and insulin resistance, which in turn have been shown to increase the risk of diabetes mellitus, cardiovascular disease and
endometrial carcinoma. During prolonged hyperglycemic exposure non-enzymatically glycated protein derivatives termed advanced glycation
endproducts (AGE) are formed at an accelerated rate and accumulate in blood and tissues. AGE accumulation induces the expression of its cognate
transmembrane receptor (RAGE) (1). Studies have shown that the AGE-RAGE signalling pathway is a major factor in complications associated with
diabetes. In UK, which had 2 million diabetes sufferers in 2000, will have a further 1 million by 2010, a 50% increase (British Heart Foundation and
Diabetes UK). Also, about 1 in 10 women in the UK develops PCO syndrome. Interestingly, young normoglycemic woman with PCOS exhibit higher
blood levels of AGEs and increased expression of RAGE in circulating monocytes and poly-cystic ovaries (2,3). We have preliminary evidence
showing that RAGE is expressed in endometrial epithelial cells and its expression is regulated by AGE, estrogens and its antagonists (Tamoxifen).
Moreover a link between RAGE levels, PCOS and endometrial carcinoma can be identified as part of our studies. This project aims to study and
characterize the RAGE signalling pathway in normal and PCOS endometrium using samples donated by volunteer patients visiting their Gynaecologist
at Singleton hospital. This research will reveal the influence of RAGE induction in the outcome of fertility for PCOS patients and the factors that can
influence the progression from PCOS to endometrial carcinoma.
How does object functionality affect the kinematics of reaching and
grasping in stroke patients?
£56,520
Dr R Martyn Bracewell
Bangor University
The objective of the research is to look at how the goal of a reaching and grasping task affects the movements of the affected arm and hand
(referred to as the ‘upper limb’) in stroke patients. The aim is to increase understanding of the motor control of the upper limb affected by stroke so
as to improve recovery for patients.
Studies suggest that at present only 5-12% of stroke patients make a full recovery in the upper limb and that the upper limb rehabilitation process
is under-researched and neglected in therapy. It has also been argued that the dominant approach used in the rehabilitation of movement in stroke
patients has a poor evidence base and fails to actively engage the patient’s motivation and attention in therapy tasks.
In the treatment of the upper limb this may be a particular limitation as research suggests that goal-directedness and higher-level understanding
play a large role in the guidance of upper limb movements. This research proposes therefore to explore these aspects of motor control in the upper
limb affected by stroke.
We will examine the upper limb movements of stroke patients performing a series of reaching and grasping tasks. The first task will involve reaching
for a functionless laboratory object. The second will involve reaching for a functional object, for example a mobile phone. The movements of the arm
and hand will be measured on both tasks, a technique known as kinematic analysis. We hypothesise that the more functional and meaningful
reaching task will lead to increased efficiency and accuracy in the movements of the affected limb. Ultimately we hope our findings will improve our
understanding of the most appropriate objects and tasks to use in the rehabilitation of the arm and hand weakened by stroke.
Phenotype/Geenotype studies in neurological syndromes co-morbid with
epilepsy and neuronal migration disorders
£59,810
Professor Mark Rees
Swansea University
The central nervous system is a complex network of nerve cells (neurones) whose primary function is to communicate messages. This
communication occurs at specialised sites of contact (synapses). At synapses, an arriving nerve impulse causes the release of a chemical which then
interacts with receptor molecules embedded in the cell membrane of a neighbouring neurone. The biological mechanisms that regulate synaptic
transmission and neuronal communication are important in understanding normal and diseased states of the brain. Genetic changes (mutations) in
the genes that control this process can cause forms of brain-cell migration disorders and movement disorders such as startle disease
(hyperekplexia), all of which have components of epilepsy in patients. These three neurological disorders are a research focus for the Wales
Epilepsy Research Network (WERN) and in terms of hyperekplexia research, WERN is a global reference centre for the genetics of this disorder. This
PhD project will concentrate on two major themes. First, is establishing the clinical and genetic trends in patients with hyperekplexia by further
investigating receptor and transporter systems. The research will validate whether new and known gene mutations are truly disease-causing,
towards the goal of informed diagnosis for affected patients and families. Secondly, we will analyze new genes involved in neuronal migration
disorders, a group of human diseases in which the process of cell migration of neurones during foetal brain development is disrupted. A particular
severe neuronal migration disorder is lissencephaly, a disorder associated with mental retardation and severe epilepsy. In collaboration with the
Institute of Medical Genetics in Cardiff University we will investigate a recently-discovered genetic cause of lissencephaly: mutations in the gene for
a protein called tubulin. We therefore aim to find whether tubulin mutations are a significant cause of the disease in the UK and assess tubulin
proteins in their cell migration role.
Defining the role played by PTPN22 in regulating the immune response
£60,000
Dr R James Matthews
Cardiff University
The body’s immune/defence system is finely balanced to ensure the efficient clearance of pathogens like bacteria and viruses but not at the expense
of inflicting damage on itself. For the majority of us this fine balancing act works extremely well. However, certain individuals are at risk for
autoimmune diseases like type I diabetes and rheumatoid arthritis because the controls governing the immune response are set incorrectly and the
immune system becomes activated inappropriately leading to the destruction of one’s own tissues. From studying autoimmune disease occurrence
in twins it is known that alterations in certain genes can place an individual at greater risk of developing autoimmune disease but until recently the
identity of the genes involved has not been determined. Following the sequencing of the human genome, large-scale studies have been performed
to identify those genes implicated in autoimmune disease. Recent landmark studies have shown that alterations in the gene encoding an enzyme
termed PTPN22 can be a significant risk factor for developing autoimmune disease. The striking aspect of these findings is that PTPN22 is a
significant risk factor for several autoimmune diseases including type I diabetes and rheumatoid arthritis. As PTPN22 is found exclusively in cells of
the immune system and has been linked to autoimmune diseases affecting different tissues, the implication is that PTPN22 alters the risk of
developing autoimmune disease by influencing the immune response. Attention is now focused on understanding the roles played by PTPN22 in
regulating immune responses, in particular identifying the specific cells within the immune system that are critically affected by changes in PTPN22
activity that consequently leads to the development of autoimmune disease. The long-term ambition of this project is that an increased
understanding of PTPN22 will have an impact on the development of improved treatments for several autoimmune diseases.
Towards a Nano Medicine based on broad spectrum topical virucidal
theraputic system
£60,000
Dr Charles Heard
Cardiff University
There is an urgent need for new topically applied products for the early intervention and treatment of a range of epithelial viral infections. For
example, it is estimated that ~90% of the population are persistently infected with Herpes simplex virus. Currently, the most frequently used
treatment is Zovirax® (containing the drug acyclovir) which needs to be applied at 4-hourly intervals and should be used prior to the appearance of
blistering. This gives rise to compliance issues, and coupled with poor skin absorption properties, means there is much scope for improvement.
Currently, products that either are, or contain, components of natural origin are popular among the general public. This proposal concerns a
potential new product for treating viral infections based upon pomegranate rind extract (PRE). When activated with iron, PRE undergoes a complex
reaction that is already known to be very potent against viruses. However, the reaction is rapid leading to problems in formulating the system in a
stable manner. This puzzle was recently solved, primarily by the applicant as part of her undergraduate research project, and relies on iron being
retained within liposomes (stable fat droplets) within a matrix of PRE only to be released for combination when the temperature is correct – ie at the
skin surface. The current proposal is a rationally designed program of developmental work that seeks to gain further information in support of the
pre-clinical efficacy of this system. Promising outcomes will benefit the Welsh nation in a number of ways: firstly, in terms of improved health due to
the availability of a broad-spectrum, efficacious product; secondly, reduced burden on health professionals due to post-viral complications and
thirdly, an opportunity for the establishment of a new commercial organisation within Wales with wealth- and employment-creating potential.
Implementation of computerised clinical decision support in a pre hospital
setting: processes of adoption and impact on paramedic role and practice
£61,165
Professor Helen Snooks
Swansea University
With increasing computerisation of management and clinical information systems in the health service, ambulance services in England and Wales are
planning the implementation of electronic patient report forms for crews to use on scene, in place of the paper forms currently in use. This
development allows the introduction of computerised clinical decision support (CCDS) systems to assist ambulance crews to assess and triage
patients to appropriate care. If ambulance crews are able safely to make decisions to leave patients at home rather than automatically take them to
A&E, patients may receive more appropriate care in the community and avoid hospital admissions - currently a key objective for the NHS.
Two Ambulance Services, Welsh and Great Western, are taking part in a randomised controlled trial of CCDS for paramedics to assess older patients
who have fallen on-scene, with the option of referral to a community based falls service. Research has shown that these patients are frequently left
at home by their attending crews and are at high risk of falling again, injury, and death. This study - the SAFE trial – is funded by the Department of
Health and aims to assess the costs and benefits of this new model of care for patients and the NHS.
This PhD proposal is for an embedded study within the SAFE trial focussing on implementation of the CCDS, and its adoption by paramedics. The
study will assess how paramedics use the CCDS, and its impact on how care is delivered. Operational indicators such as time spent with the patient
and proportion of patients taken to hospital, will be compared between paramedics who are using the CCDS and paramedics providing care as usual.
Set against this context, an in-depth exploration of factors affecting use of the CCDS will be carried out, through focus groups and individual
interviews with paramedics and service managers.
Evaluation of the adoption of the CCDS by paramedics will provide valuable information for implementing electronic clinical data capture systems in
the future, in this setting and more widely.
Factors pertaining to the occurrence of hypoglycaemia in exercising type
1 diabetes patients
£68,324
Dr Richard Bracken
Swansea University
Welsh individuals with diabetes are advised to take regular exercise as part of a healthy lifestyle. However, patients face an increased risk of
hypoglycaemia during and after exercise which may predispose those individuals to syncope, coma or even death. Strategies to prevent exerciseinduced hypoglycaemia in patients with Type 1 diabetes mellitus (T1DM) are unclear. Providing definitive advice on insulin therapy and feeding
strategies prior to exercise participation is complex, in part due to the interactions of different insulin preparations, different doses, food intake and
timing of administration prior to exercise. With local research ethics approval, patients with T1DM will be recruited for a series of experiments
examining the impact of; (i) reductions in the dosage of insulin prior to performing aerobic exercise; (ii) changes in the type of ingested
carbohydrate prior to performing a bout of exercise and (iii) alterations in the timing of insulin administration and carbohydrate feeding on the postexercise glucose concentrations. Patient’s ventilatory responses will be measured during exercise and the amount of glucose oxidised will be
calculated. Blood samples will also be taken before and after exercise to determine the glucose (and other metabolite) changes post-exercise. With
the increasing number of young type 2 patients and the aim for tight glycaemic control and hence increased use of
insulin, the results from this study would be applicable to a significant
proportion of the 5% of the Wales population who have diabetes (Welsh Health Service report 2002). Therefore, controlled studies on the effects of
the above-mentioned factors on T1DM patients undergoing physical exercise is warranted. The study will generate information on avoiding the
occurrence of hypoglycaemia (secondary prevention) and avoiding or delaying complications (tertiary prevention) associated with long term
hyperglycaemia.