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Illingworth's
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Final Year Undergraduate Projects 2010 - 2011



Dr. J.A.Illingworth:

This page provides more detailed information about the final year undergraduate research projects available under my supervision during 2008 - 2009 academic year.

Childhood obesity in Leeds: (laboratory [field] project)

Children in the inner city have 10 times the child road accident rate when compared with the outer suburbs, and recent preliminary evidence in Leeds suggests that they might have double the incidence of childhood obesity when compared with children in the outer areas of Leeds.

This may be because inner city children lack safe opportunities for physical recreation and play. This is the hypothesis to be tested.

Using a combination of mapping software, interviews and observations of children engaged in physical recreation and play, students will attempt to establish (1) whether there are any measurable differences in childhood physical activity in different areas of Leeds, (2) whether this reflects differing opportunities for physical recreation, and (3) whether this correlates with other outcomes, such as injuries and obesity.

Possible extension: kid’s diets and “junk food”. One possibility is to lend children mobile camera phones to record their play activities and diet, thereby avoiding the problems of child interviews and imperfect recall. I doubt that we have the budget for this, but I will try to seek support from a mobile phone company.

You must pass a CRB check with the Criminal Records Bureau before you are allowed to interview children for this project.

Chaotic behaviour during gene expression: (computer project)

The negative feedback systems regulating gene expression have all the physical and mathematical features which can give rise to chaotic behaviour in other physical systems. It is hypothesised that chaotic gene expression would not normally offer any biological advantages, and that mechanisms will probably have evolved to prevent it happening.

Theoretical arguments suggest that chaos could be best avoided by reducing the sensitivity of the feedback loops, and by reducing any delays between the sensing mechanism and the biological response. These have implications for the "design" and evolution of biochemical control mechanisms. It may be possible to prove that the mixture of allosteric, covalent modification and genetic control systems observed in many organisms should outperform any of the three mechanisms used in isolation. It seems possible that the attentuation systems often associated with polycistronic bacterial mRNA could be particularly effective in avoiding chaotic behaviour.

Students will use computer model building to test these hypotheses [either Excel spreadsheets or direct coding in C++] and construct model systems lacking one or more of the normal biological features to see how well these are expected to behave.

Mitochondrial metabolism: (computer project)

Many of the technical problems previously associated with metabolic computer models have been solved in recent years. However, a whole cell is still a very large and complex system, and it is difficult to assemble a sufficient quantity of reliable metabolic data to properly distinguish between alternative models. This project will focus on the mitochondrial compartment, which is much smaller and simpler than a complete cell, so there is a greater prospect of useful results within a reasonable period of time.

Dilated cardiomyopathy: (library project)

Dilated cardiomyopathy (DCM) is a severe, debilitating disease which is the most common indication for cardiac transplantation. It is characterised by huge increases in cardiac chamber size, ventricular wall thinning, and a loss of cardiac contractility. The dilatation may give rise to heart valve incompetence, further reducing the pumping efficiency of these diseased hearts. Systemic and pulmonary venous blood pressures are elevated, leading to fluid oedema in the lower limbs and to respiratory difficulties, which may be compounded by deep vein thrombosis and pulmonary embolism.

A bewildering variety of defects and insults give rise to the same end-stage pathology. A substantial minority of cases have an obvious genetic contribution, with identified mutations in cardiac structural proteins. For the majority of cases the precise cause remains unknown. This unpleasant disease is sometimes preceded by a Coxsackie virus infection, and may include an auto-immune component. Suggested auto-antigens include the mitochondrial adenine nucleotide carrier, cardiac myosin and the cardiac catecholamine receptor. However, in many patients it is difficult to demonstrate any tissue inflammation or immune response.

There is no known cause for the unwanted cardiac re-modelling which is such a conspicuous feature of this disease. A suggested thrust for this library project is to look at the mechanisms responsible for morphogenesis in normal hearts, in order to understand how these might give rise to the re-modelling seen in diseased hearts.

Inflammation & ageing: (library project)

Inflammation has long been recognised as an important physiological process, particularly in response to infection and traumatic injury. Recently there has been a growing recognition that inflammation and the pro-inflammatory cytokines IL-1 IL-6 and TNF-α play major pathological roles in a much wider range of conditions, including the so-called "diseases of civilisation". Inappropriate inflammation is a major cause of the death and ill-health in all areas of the world, and attempts to control inflammation are a major reason for drug treatment. It is arguable that an aberrant inflammatory response is the dominant pathological process in the human body.

It is possible to get some idea of current research activity in these areas by counting "Web of Science" hits for each disease between January 2002 and March 2003. Some results are tabulated below:

pathologytotal publications
Jan 02 to Mar 03
papers mention
inflammation
percent
Alzheimer's disease48753116.4
arthritis6484186328.7
asthma5129146528.6
atherosclerosis504389817.8
cachexia2715821.4
cancer4786115353.2
cardiomyopathy26171405.3
coeliac disease6689714.5
cholecystitis2222410.8
Crohn's disease125273959.0
diabetes122245474.5
emphysema5008717.4
glomerulonephritis106517416.3
heart failure49462254.5
hypertension101254144.1
multiple sclerosis256357422.4
obesity47521693.6
pancreatitis154924115.6
pre-eclampsia264124.5
hemorrhagic fever26593.4
hyperthyroid545162.9
hypothyroid799232.9
vasculitis104725424.3
Totals11506698758.6

Students will initially review the molecular biology of the "classical" inflammatory response, before examining recent research on inappropriate responses that may form part of the ageing process.

Nucleoside diphosphate kinase: (laboratory project)

It is well established that ATP has a different phosphorylation potential in different parts of the same cell. This situation arises because the concentrations of [ATP], [ADP] and [Pi] differ in the various cell compartments. As a result the reaction

is further from equilibrium (i.e. more negative delta G for ATP hydrolysis) in some cell compartments than in others.

Metabolite transport across sub-cellular membranes makes a significant contribution to these effects. ATP is initially manufactured at a relatively low phosphorylation potential (i.e. at a lowish ATP:ADP ratio) by ATP synthase within the mitochondrial matrix space. It is subsequently transported into the cytosol by the adenine nucleotide carrier, which swops an ATP4- for an ADP3-  and is consqently driven in the direction of ATP export by the mitochondrial membrane potential. This means that the cytosol has a higher ATP:ADP than the mitochondria, and ATP is "worth more" in the cytosol.

Until recently it was assumed that all the other nucleoside triphosphates had more or less the same phosphorylation potential as ATP, and that all were ultimately derrived from ATP through reactions catalysed by nucleoside mono- and di-phosphate kinases. However, there are reasons to doubt this simplistic view.

GTP is manufactured during the TCA cycle by the enzyme succinate thiokinase (STK) which catalyses the reaction:

A nucleoside diphosphate kinase (NDK) is required to transfer the high-energy phosphate to ADP in the reaction:

Unfortunately, the STK is in the mitochondrial matrix space, but it seems likely that NDK is in the intermembrane space, with no direct communication between the two enzymes. In addition, there are other GTP-linked enzymes in the matrix space, such as PEP-carboxykinase, fatty acid activation and a nucleoside MONOphosphate kinase:

which might suggest that the intramitochondrial GTP and ATP pools are kept apart, and that GTP has a higher phosphorylation potential than ATP inside the matrix space. This could be important for successful gluconoegenesis under conditions of metabolic stress (running for your life, for instance). The reaction sequence

could behave as a "metabolic transformer" converting two low grade ATP-type phosphoanhydride bonds into 1 high potential GTP-type phosphoanhydride bond suitable for the manufacture of PEP, which is a much better phosphate donor than ATP.

The general strategy would be (1) to get the various enzyme assays working, and confirm the suspected position [pedestrian, but gets results in the bag early on] then (2) show by immunoblot or otherwise that the intra-and extra-mitochondrial forms of NDK and PEPCK really are different (either different genes or different splicing) and that there is not a dual intracellular location, and (3) look for evidence of compartmentation in mitochondrial nucleotide metabolism.

Tropical Diseases: (library project)

This is a huge field and there are many diseases to choose from. I suggest you pick out one, or a closely related group. In recent years students have prepared reports on various aspects of Malaria, Chagas disease, Leishmaniasis, Schistosomiasis, Sleeping Sickness and Dengue fever but progress is now so rapid that it would be possible to pick these topics again. There is a lot of basic information in the Leeds Medical School Library, but if you want a quick overview of the various diseases, try the WHO website (there is a group entry for tropical diseases in the alphabetical listing) or the CDC website in the USA.

There is a really excellent account of African Trypanosomiasis by Moore et al (2002) NEJM 346, 2069-2076. You might be asked to log in to this journal website, in which case the Health Sciences Library can supply a password.

There are several parasitology sites on the web, including (for example) David Gibson's website and a useful introduction from Leicester.

Many of these diseases have several things in common. The parasites are often protozoal, except for tuberculosis, leprosy and viral diseases! They often show antigenic variation, suppress the host immune system, or steal surface antigens from their hosts. This may lead to autoimmune complications. Several parasite and vector genomes have been sequenced and this has suggested new drug targets which exploit differences between parasite and host metabolism.


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